Method And Device For Drug Delivery

ABSTRACT

Systems, devices and methods for delivery of a chemical substance to the body of the patient are provided. Such embodiments may include an infusion catheter configured to be inserted into tissue, a catheter securing element configured to be adhered to the skin of the patient and further configured to secure the infusion catheter to the skin, a drug delivery pump configured to infuse a drug into the infusion catheter for delivery to a drug infused region on the body of the patient, and a treatment element configured to apply a treatment to the drug infused region to improve pharmacodynamics of the drug during a period of delivery of the drug to the patient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/895,518, filed Mar. 19, 2007, U.S. Provisional PatentApplication Ser. No. 60/895,519, filed Mar. 19, 2007, U.S. ProvisionalPatent Application Ser. No. 60/912,698, filed Apr. 19, 2007, U.S.Provisional Patent Application Ser. No. 60/940,721, filed May 30, 2007,U.S. Utility patent application Ser. No. 11/821,230, filed Jun. 21,2007, U.S. Provisional Patent Application Ser. No. 61/008,278, filedDec. 18, 2007, U.S. Provisional Patent Application Ser. No. 60/956,700,filed Aug. 19, 2007, U.S. Provisional Patent Application Ser. No.60/970,997, filed Sep. 10, 2007, U.S. Provisional Patent ApplicationSer. No. 61/008,325, filed Dec. 18, 2007, U.S. Provisional PatentApplication Ser. No. 61/008,274, filed Dec. 18, 2007, and U.S.Provisional Patent Application No. 61/008,277, filed Dec. 18, 2007. Eachof the foregoing disclosures are incorporated by reference herein in itsentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to systems and methods for deliveringdrugs to a patient. In particular, the present invention relates tosystems and methods for subcutaneous infusion of drugs or substances andusing energy sources to improve effectiveness of the infused drugs.

2. Background of the Invention

Diabetes is a very serious illness affecting millions of people today.Many diabetic patients require injection of insulin to maintain properlevels of glucose in their blood in order to survive. Such injections ofinsulin are done using drug delivery systems.

Many medical treatment systems and methods involve drug delivery systemsthat employ subcutaneous infusions of therapeutic fluids, drugs,proteins, and other compounds. Such delivery systems and methods,especially in the area of insulin delivery, have made use ofsubcutaneous catheters and continuous subcutaneous insulin infusion(CSII) pumps. In conventional insulin pumps, the pump is configured tobe attached to a disposable thin plastic tube or a catheter throughwhich insulin passes into the tissue. The catheter can be insertedtranscutaneously, typically on the patient's abdomen, and is changedevery two to three days. New types of insulin pumps, such as the OmniPodpump manufactured by Insulet Corporation, do not have an externalcatheter and, but rather, a catheter port that is embedded into the pumpmechanism.

In many instances, the patients require insulin delivery around theclock to keep proper levels of glucose in their blood. Insulin can bedelivered at a basal rate or in bolus doses. The basal rate representsinsulin that is continuously delivered to the patient. Such continuousdelivery of insulin keeps patient's blood glucose in the desired rangebetween meals and over night. The bolus dose is an amount of insulindelivered to the patient matching a dose of carbohydrates consumed bythe patient to address increased glucose levels as a result of theingested food. Some conventional pump mechanisms are configured to reactupon command, or by way of an algorithm, to the increase in glucoselevels by delivering a bolus dose of insulin that matches the rise inthe level of glucose and prevents large glucose excursions. However,many conventional subcutaneous drug delivery systems are incapable ofquickly matching or preventing the rise of blood glucose. The delay insuch matching is also true in case of the “rapid-acting” insulin. Someof the reasons for this delay include a lag in the absorption of insulinfrom the injection site and the time it takes for complex insulinmolecules to break down into monomers.

Additionally, since blood glucose levels rise immediately following themeal, the delay in matching insulin to the rising levels causes postprandial hyperglycemic events (i.e., when levels of blood glucose areabove normal) to occur. Further, occasionally after a certain period oftime passes (e.g., 2-3 hours) after a meal, the blood glucose levelsdrop yet insulin concentrations in the blood rise followed by the peakof the systemic insulin effect and result in causing hypoglycemic events(i.e., when levels of blood glucose are below normal) to occur. Bothhyperglycemic and hypoglycemic events are highly undesirable.Additionally, since the local blood perfusion at the insulin infusionregion has large variations depending on the ambient temperature andother parameters, it induces large variations to said delay of the peakof time profile of the insulin action. Those variations in the insulinpeak action period further increase the variability in the blood glucoselevel.

Thus, it is desirable to provide a system and a method that providesefficient and timely delivery of the drug to the patient. In particular,it is desirable to provide a system and a method for delivering insulinto the patient that improves effectiveness of insulin in the blood tomaintain normal levels of blood glucose and prevent or reducehyperglycemic and hypoglycemic events.

SUMMARY OF THE INVENTION

Embodiments of the present invention relate to systems, devices andmethods for delivery of drugs, substances and/or chemicals (together“drugs” or “substances”) to a patient and for improving theeffectiveness of such drugs once they are delivered. In someembodiments, of the present invention, a device for improvingperformance of catheter-based drug delivery devices is provided. Thecatheter can be an adjunct to a pump or embedded into the pumpmechanism. In such embodiments, the device can be applied to thevicinity of the tissue region of the patient into which a drug (e.g.,insulin) is delivered, to expose the tissue region to a treatment asheat, cooling, temperature control, mechanical vibrations, suction,massaging, acoustic stimulation (e.g., ultrasound), electromagneticradiation, electric field, magnetic field, radio frequency irradiation,microwave irradiation, electrical stimulation, or the like, or anycombination of the above treatments to improve the drug'spharmacokinetic and/or pharmacodynamic profile. The tissue treatmentelement may stimulate or inhibit tissue by introducing secondarysubstances for example including but not limited to drugs, medicament,chemical, biologically active bacteria, biologically inactive bacteriaor the like or also. any combination of the above treatments to improvethe drug's pharmacokinetic and/or pharmacodynamic profile.

Such a device, according to some embodiments of the present invention,can also be part of a catheter which has one section inside the tissueand another section that connects to a unit outside the tissue (i.e., atranscutaneous delivery system). As can be understood by one skilled inthe art, properties (such as amplitude, phase, frequency, etc.) of theindividual excitation source(s), the combination of excitation sources,the relative ratio and timing between the various excitation sources,may be controlled by a processor in order to achieve a desired responseof the tissue region next to the catheter. The sources can also beadjusted according to the chemical/physical properties of the infusedsubstance.

In some embodiments, of the present invention, a device for supplyingenergy to a tissue region (or infused region) can be configured tomonitor and control the properties of the excitation sources (such asamplitude, phase, intensity, frequency, etc.). Based on the monitoring,the information can be provided to a controller (“controller”, alsoreferred to as a “processing unit”) that uses the information to reducethe variability of the drug delivery process. In such embodiments, thedevice can be configured to monitor properties of the tissue next to thecatheter element (e.g., such as temperature). Based on such monitoring,the information can be provided to the controller that utilizes theinformation to improve the pharmacokinetic and/or pharmacodynamicprofile of the drug in the desired direction as well as performance andreduce variability of the drug delivery process.

The device according to some embodiments of the present invention can beconfigured to either automatically detect the drug delivery through thecatheter by the delivery apparatus, get a signal from the drug deliverydevice, get the signal from a separate button or switch to initiate aprotocol of exposing the infused tissue region to the above describedtreatments or tissue stimulations. The device can then be configured tobegin operating by applying a stimulation or a treatment to the tissue.The tissue response to the stimulation enhances the functionality of adrug delivery pump by enhancing the kinetics of molecule transportbetween the catheter tip placed inside the tissue to the variouscompartments of the tissue region around it and to the blood system.

In some embodiments, the applied treatment may reduce the variability ofthe drug absorption in the blood or lymph system and its local andsystemic effects. For example, heating the tissue region in the vicinityof the area of drug delivery (i.e., infused region) to a presetregulated temperature during the drug infusion and absorption into theblood may make local blood perfusion at that region more reproducibleand the drug absorption process more uniform and reproducible as well.Also, by reducing the delay between the drug delivery into the tissueand absorption into the blood system, the variability of the drug actioninduced by the delayed profile can be reduced. The temperature of theregion adjacent to the infusion region can be regulated for longerperiods, but the cost may be the energy source volume and weight.Therefore, for minimization of the energy source size the heating periodshould be optimized in relation to the period of the drug infusion andabsorption into the blood.

In some embodiments, the tissue treatment or stimulation device may betriggered manually by the user. The user may activate the treatmentdevice or devices before or after the pump activation to enhance thetissue response to the delivered drug. In such embodiments, this can bedone by pressing a button or a sequence of buttons on the tissuetreatment device. In some embodiments, in case of communication betweenthe drug delivery device and the treatment device, the treatment can betriggered manually by pressing a button or a sequence of buttons on thedrug delivery device. For example, in case of an insulin pump, the pumpmay have a special button for triggering a “fast bolus” compared to theother bolus options provided by the pump. The fast insulin bolus modecan be configured to start one of the disclosed treatments in parallelto application of the insulin bolus infusion for a given period of time,such as 30 minutes (for example). This improves or modifies (in anadvantageous manner) insulin's pharmacokinetics or pharmacodynamics,tissue blood perfusion and/or absorption in the blood and is highlyattractive in conjunction with high glycemic index food. Application ofa “fast bolus” may be useful in consumption of high glycemic index foodwhere larger rapid glucose excursions occurs, but also in most of thecases of using insulin boluses for prandial coverage. Application of a“fast bolus” can be initiated by pressing a special sequence of buttonsor choosing a bolus mode using the pump display and buttons. In someembodiments, the user may trigger the tissue treatment or stimulationbefore the application of the bolus to further improve the treatmenteffect. In some embodiments, the user may trigger the tissue treatmentor stimulation together with the infusion of the insulin bolus beforethe meal to further increase the treatment effect. In some embodiments,the tissue treatment or stimulation may be triggered after the bolus tosave battery life.

Some embodiments of the present invention also provide methods formonitoring tissue parameters non-invasively or invasively using thecatheter or both invasively and non-invasively, and using theinformation to control activation of the device of the present invention

Some embodiments of the present invention also provide methods forimproving or modifying a drug's pharmacokinetic and/or pharmacodynamicprofile in order to reduce time to peak action in the blood of theinjected material by applying a modulation pattern to the pump. Withthis modulation, the infusion fluid is slightly pulled in and out of thetissue during or after the drug infusion process. In such embodiments,this method may not require an addition of any other devices to thecurrent infusion pump rather it can be configured to modulate drug flowfrom the drug delivery element or pump.

In some embodiments, a drug delivery pump may be mechanically orelectronically connected to the catheter of the above-noted deviceembodiments. In such embodiments, the catheter unit includes at leastone of the following excitation sources or at least one combination oftwo such sources from the following: a heat source (e.g., a heatresistor), a suction port activated by a pump (for example), amechanical vibration source, an ultrasound excitation source, anultrasound transducer, a light source, an optical fiber, a massagingelement, electromagnetic radiation source and/or a combination of atleast two of sources of heat, vibrations, suction, ultrasound, light,electromagnetic radiation and massaging.

In some embodiments, a device for drug delivery is provided whichincludes an infusion catheter for insertion into tissue, a drug deliverydevice for infusing the drug into and within the infusion catheter, atreatment device for applying a specific treatment or stimulation to thedrug infused region in order to improve drug's pharmacokinetic,pharmacodynamic profile and/or to increase blood perfusion in thatregion during the drug delivery period to improve drug absorption intothe blood system.

In some embodiments, a device for drug delivery is provided whichincludes an infusion catheter for insertion into tissue, a drug deliverydevice for infusing a drug into the infusion catheter, a treatmentdevice for applying a specific treatment or stimulation to the druginfused region in order to improve, modify and/or stabilize the drugpharmacokinetics, pharmacodynamics, and/or to reduce variations of thedrug absorption into the blood system.

In some embodiments, a device for drug delivery is provided and includesan infusion catheter for insertion into tissue, a drug delivery devicefor infusing a drug into the infusion catheter, a treatment device forapplying a specific treatment or stimulation to the drug infused regionto improve, modify and/or stabilize the drug's pharmacokinetics,pharmacodynamics and/or to reduce variations of the drug absorptionprocess into the blood system, at least one sensor to measure the effectof the treatment device, and a control unit to control the operation ofthe treatment device using the information from the at least one sensor.

In some embodiments, a device for drug delivery is provided and includesan infusion catheter for insertion into tissue, a drug delivery devicefor infusing a drug into the infusion catheter, a sensor for detectingdrug infusion through the catheter either directly or indirectly, atreatment device for applying a specific treatment to the drug infusedregion to improve, modify and/or stabilize the drug pharmacokinetics,pharmacodynamics and/or to reduce variations of the drug absorptionprocess into the blood system, and a control unit for initiating atreatment profile with the treatment device after detection of the druginfusion with the sensor.

In some embodiments, a device for drug delivery is provided thatincludes an infusion catheter for insertion into tissue, a drug deliverydevice for infusing a drug into the infusion catheter, a housing for thedrug delivery device, a sensor built into the housing to sense theoperation of the infusion device upon a drug bolus being delivered bythe device, a treatment element for applying a specific treatment to thedrug infused region to improve, modify and/or to stabilize the drugpharmacokinetics or pharmacodynamics, an electronic control unitconnected to the treatment element for initiating a treatment profilewith the treatment element when the drug delivery device starts druginfusion. In some such embodiments, the unit is built into the housing.

In some embodiments, a device for drug delivery is provided thatincludes a drug delivery device, an infusion catheter for insertion intotissue. The infusion catheter is part of an infusion set including: aninfusion catheter, a tube with or without connections that connects theinfusion catheter to the drug delivery device, a treatment element forapplying a specific treatment to the drug infused region of the tissueto improve, modify and/or stabilize the drug pharmacokinetics orpharmacodynamics, an adhesive element that is used to secure thetreatment element and/or the infusion catheter to a position over thetissue, a communication channel between the drug delivery device and thetreatment element, a control unit (i.e., a controller/processing unit)that initiates a treatment profile with the treatment element when thedrug delivery device starts drug infusion. The elements of the devicemay be all or part contained in the same housing.

In some embodiments, a device for drug delivery is provided whichincludes a drug delivery device, and an infusion catheter for insertioninto a tissue. The infusion catheter may be part of an infusion setincluding: an infusion catheter, a lube with or without connections thatconnects the infusion catheter to the drug delivery device, a treatmentelement for applying a specific treatment to the drug infused region ofthe tissue to improve, modify and/or stabilize the drug pharmacokineticsand/or pharmacodynamics, an adhesive element for securing the treatmentelement and/or the infusion catheter to a position over the tissue, ahousing for the drug delivery device, a pickup coil or other sensorbuilt into the housing to sense the operation of the infusion devicewhen a bolus dose is delivered by the device, and a control unit thatstarts a treatment profile with the treatment element when the drugdelivery device starts the drug infusion. The unit is built into thehousing.

In some embodiments, a device for drug delivery is provided whichincludes an infusion catheter for insertion into tissue. The infusioncatheter may be part of an infusion set including: an infusion catheter,a tube with or without connections that connects the infusion catheterto the drug delivery device, a treatment element for applying a specifictreatment to the drug tissue infused region to improve, modify and/orstabilize the drug pharmacokinetics and/or pharmacodynamics, an adhesiveelement that is used to secure the treatment element and/or the infusioncatheter to a position over the tissue, a housing for the drug deliverydevice, and a control unit that starts a treatment profile with thetreatment element when the drug delivery device starts the druginfusion.

In some such embodiments, the adhesive, the treatment element and theinfusion set are disposable while all other components are reusable. Insome embodiments, the adhesive, the treatment element, the infusion setand the control unit are disposable while all other components arereusable. In some embodiments, all components including the infusiondevice and the power source (batteries) are disposable. The aboveelements of the device in the present invention such as the drugdelivery device, the infusion catheter, the treatment device and othersmay be separate individual elements or elements contained all or part ofthem in one housing.

Some embodiments of the present invention provide for a device forimproving the performance of drug delivery devices by delivering a drug(e.g., insulin) in conjunction with the application of electromagneticradiation treatment, e.g., from a source of electromagnetic radiation.In some embodiments, the drug delivery device includes a catheter baseddrug delivery device. Various implementations of the catheter and thedrug delivery device are encompassed within the present disclosure. Forexample and without limitation, the catheter may include an externalelement to the pump or an element partially or completely embedded intoa pump mechanism. The device described herein can be part of thecatheter which has one section inserted inside the tissue and anothersection that connects to a unit outside the tissue.

The electromagnetic radiation treatment is, in some embodiments, appliedto a tissue region to which the drug is delivered to expose it toelectromagnetic radiation and/or to an effect caused by electromagneticradiation to improve the drug pharmacokinetics or pharmacodynamics. Theeffect may include, for example, acoustical stimulation throughapplication of electromagnetic radiation, light based stimulation andthe like.

The radiation source properties, or the combination of a radiationsource and another stimulation source as described in at least U.S.Provisional Application Nos. 60/912,698, 60/895,519, 60/956,700,61/008,325, 61/008,277, 60/940,721, and 61/008,278, the disclosures ofwhich are incorporated herein by reference in their entireties as iffully set forth herein, may be controlled by a controller to achieve adesired response of the tissue region next to the catheter. Suchadjustment to the chemical/physical properties of the infused substancemay also be made. Furthermore, one or more adjustments may be madeaccording to the properties of each stimulation source (such asamplitude, phase, frequency and the like) as well as the relative ratioand timing between the various stimulation sources.

The present disclosure also provides, in some embodiments, a method formonitoring the properties of the stimulation or the properties of thestimulated tissue region. such monitoring is performed through a monitorwhich provides data and/or feedback to the above controller. Thecontroller uses the information to reduce the variability of the drugdelivery process, for example to improve the pharmacokinetic and/orpharmacodynamic profile of the drug as well as performance and reducevariability of the drug delivery process.

In some embodiments, monitoring may be performed by monitoring theproperties of the tissue next to the catheter element (including but notlimited to tissue blood perfusion, temperature, concentration of one ormore blood components) and/or monitoring the resultant effect ofstimulating the tissue, for example, monitoring the back reflectedradiation from the tissue.

In some embodiments, drug delivery is performed through a deliveryapparatus, which may be any type of delivery apparatus known in the art.In some embodiments, the device receives information regarding drugdelivery. Such information may be provided through automatic detectionof drug delivery through the catheter by the delivery apparatus and/orby receiving a separate signal from the drug delivery device or from aseparate button or switch. Regardless of how detection is performed,detection of drug delivery is used to initiate a protocol of exposingthe infused tissue region to the above described radiation treatments ortissue stimulations.

Upon detection, the source of electromagnetic radiation applieselectromagnetic radiation to the tissue to be treated. The tissueresponse to the stimulation enhances the functionality of the drugdelivery pump by, for example and without being limited by a singlehypothesis, enhancing the kinetics of molecular transport from thecatheter tip placed inside the tissue to the various compartments of thetissue region around it and to the blood system. In some embodiments,the applied electromagnetic radiation reduces the variability of thedrug absorption in the blood system and its effect.

The present disclosure further describes, in some embodiments, a devicefor drug delivery including an infusion catheter inserted into thetissue, a drug delivery device that infuses the drug into the infusioncatheter, a treatment device that applies radiation to the drug infusedregion to improve the drug pharmacokinetics or pharmacodynamicsstabilization to reduce variations of the drug absorption process intothe blood system, at least one sensor to measure the effect of thetreatment device, and a control unit to control the operation of thetreatment device using the information from the at least one sensor.

The present disclosure further describes, in some embodiments, a devicefor drug delivery including an infusion catheter inserted into thetissue, a drug delivery device that infuses the drug into the infusioncatheter, a sensor that detects the drug infusion through the cathetereither directly or indirectly, a treatment device that applies radiationto the drug infused region to improve the drug pharmacokinetics orpharmacodynamics or to reduce variations of the drug absorption processinto the blood system, and a control unit that starts a treatmentprofile with the treatment device after detection of the drug infusionwith the sensor. According to some embodiments, the sensor is built intoa housing for the drug delivery device to sense the operation of theinfusion device when drug bolus is delivered by the device.

Some of the embodiments include a source of electromagnetic radiationfor delivering the electromagnetic radiation as described above.

The device may also include a communication channel between the drugdelivery device and the treatment element, and a control unit thatstarts tissue radiation treatment profile with the treatment elementwhen the drug delivery device starts the drug infusion.

The device may further include a housing for the drug delivery device, apickup coil or other sensor built into the housing to sense theoperation of the infusion device when drug bolus is delivered by thedevice and a control unit that starts a treatment profile with thetreatment element when the drug delivery device starts the druginfusion. The control unit is built, in some embodiments, into thehousing.

The adhesive, the treatment element and the infusion set may bedisposable while at least one or more other components are reusable. Insome embodiments, a plurality of the other components are reusable. Insome embodiments, all components are reusable. The control unit may bedisposable while all other components are reusable. The infusion deviceand the power source (batteries) may be disposable.

As used in the present application's specification, the term “drug” isdefined to include any pharmaceutically active compound including butnot limited to compounds that treat diseases, injuries, undesirablesymptoms, and improve or maintain health. The terms “targeted area” or“targeted areas”, or “target site”, as used herein, are defined toinclude a systemic bloodstream of a human body, areas of a human bodywhich can be reached by a systemic bloodstream including, but notlimited to muscles, brain, liver, kidneys, etc., and body tissue regionsproximate a location of an administered drug.

The present application is directed to the delivery of a drug (by way ofa non-limiting example—insulin) to treat any chronic or acute condition,for example, diabetes, hypoxia, anemia, cholesterol, stroke, heart orthe like.

In some embodiments of the present application the drug is injected witha syringe or mechanical pump or another drug dispensing device which isconnected to an injection port combined with tissue treatment element,when the drug is need to be injected and disconnected from saidinjection port. In some embodiments the injection port include acatheter inserted into the tissue, a securing element attached to theskin and a connector for connecting a syringe or another drug dispensingdevice.

Some embodiments of the present application provide treatments asdescribed before to the tissue vicinity of drug injection site, injectedwith regular injections, such as with a syringe and a needle.

Some embodiments of the present invention provide automatic regulationof a measurand level in a user body by controlling the amount of infuseddrug that influence measured level at the user body. For example, thereare many attempts to compose an “artificial pancreas” to control bloodglucose level, since the development of continuous glucose monitors. Inthis case, any delay such as delay of the insulin absorption and actiontime, any variability in this delay and any variability in the residualinsulin level in the body induces an error for the control algorithmthat will result in less tight glucose regulation. Thus, by applyingtissue treatment to the insulin delivery site as described by themethods and devices in the present application a better accuracy androbustness of a control algorithm that uses glucose sensor readings canbe achieved.

Some embodiments of the present invention provide for an implantabledrug delivery device for the automatic and direct introduction of a drugto a target site, wherein the drug may be introduced to an implantedcompartment from an external drug source. The implantable drug deliverydevice includes a controller, tissue treatment element, delivery member,and a drug storage compartment. The implantable device may furtherinclude an external (not implanted) user interface that provides theuser with a database, dosage form, dosage timing, and dosage trigger.The user interface may communicate with the controller usingcommunication protocols for example including but not limited towireless, cellular, optical, RF, IR or the like. The implantable drugdelivery device may further include a sensor that may be implanted withthe implanted device.

The drug storage compartment, according to some embodiments, is aninternal container or storage site that maintains the drug in useableform until it is required for delivery. The drug dosage compartment maycontain sufficient quantities of the drug to last for a prolonged periodof time, for example requiring replenishment once every 3 months or so.The drug storage compartment may receive the drug from an externalsource by direct injection into the compartment. The drug storagecompartment may receive the drug from an external source through thedrug receiving member, for example including a catheter, such that thedrug supply may be replenished when needed. The drug storage compartmentmay be subdivided into a plurality of storage compartments, for example,for different drugs.

In some embodiments, the controller functions to control the level ofdrug delivered to the target site. An implanted sensor may be coupled tothe controller for further control of the drug dosage and delivery time.The sensor may indicate to the controller the level of a measurand. Forexample, the measurand may be indicative of the glucose level,cholesterol level or the like, at least partially based on which thecontroller determines the required treatment protocol, for exampleincluding but not limited to the drug dosage to be delivered, timing ofthe drug delivery or the like.

The sensor may, according to some embodiments, be external to the drugdelivery member and used externally to measure a measurand for examplethe blood glucose level. The external sensor is coupled to a processorfor example including but not limited to a mobile telephone, PDA or thelike that is able to communicate with the controller of the implanteddrug delivery device. Sensor data is communicated to the implantedcontroller using at least one communication protocols for exampleincluding but not limited to cellular, wireless, IR, optical, RF or thelike communication protocols. For example the sensor data is a measurandthat may be indicative of the glucose level, cholesterol level or thelike. Based on the communicated sensor data, the controller determinesthe required treatment protocol for example including but not limited tothe drug dosage, timing and tissue treatment required relative to themeasured data.

In some embodiments, the controller activates or deactivates the tissuetreatment element to bring about a desired stimulatory or inhibitoryeffect that may maximize or minimize drug delivery to the target site.When the drug storage compartment requires replenishment, the controllermay communicate with an external device, for example, includingactivating an LED, email, SMS or the like using various communicationprotocols for example including but not limited to wireless, wired,optical, cellular, RF, IR or the like communication protocols.

According to some embodiments, the drug is delivered to the target siteusing a delivery member for example including but not limited to acatheter, a permeable membrane, a selectively permeable membrane, aplurality of catheters, grafted tissue, blood vessel, or the like. Asensor or tissue treatment element may be incorporated into the deliverymember.

The tissue treatment element may be used, according to some embodiments,to stimulate or inhibit tissue and the delivery site to control insulinuptake in the body to reduce the peak rise and fall of glucose levels,in order to prevent insulin starvation (prandial hyperglycemia) at thebeginning of the peak and hypoglycemia at the end of the peak. Thecontroller and tissue treatment element function together to regulatethe blood glucose cycle. The tissue treatment element may use differentmethods and devices as described by the present application to stimulateor inhibit tissue leading to increased blood perfusion that improvesinsulin absorption or similarly to reduce insulin absorption whennecessary.

Some embodiments of the present invention provide for a drug deliverydevice for the direct introduction of a drug to a target site having animplanted portion (internal) and a non implanted portion (external).Different components may be implanted for example including but notlimited to a sensor, controller, delivery member, drug production whilethe user interface, tissue treatment element or drug storagecompartment. In some embodiments, the tissue treatment element is notimplanted but is external and applies the tissue treatment to the skinabove the implanted drug delivery device. The external components maycommunicate with the internal components using protocols including butnot limited to wireless, wired, cellular, optical, IR, RF communicationor the like.

An implanted embodiment is capable of producing a drug for exampleincluding but not limited to insulin. Insulin production may be achievedby an active process, for example including but not limited to theactivity of beta cells, genetically transformed cells, tissues, or thelike live cultures or cells able to produce insulin, on demand. Thetrigger for producing and administrating the correct dose of insulin isthe glucose level which may for example be sensed by the beta cellsthemselves. The tissue or skin treatments or stimulation methods can beused to treat or stimulate a tissue region to which insulin is infusedby the insulin producing cells.

In some embodiments, the insulin producing cells may be covered orencapsulated to prevent the immune system from attacking the implantedcells. In some embodiments, the insulin producing cells may be disposedin an implanted closure or housing with additional components. In someembodiments, such as in case of implanted beta cells or other drugproducing cells, the tissue treatment element may be used to controltissue conditions that could improve the production of the implantedcells. For example, by improving local perfusion the cell has increasedavailability of oxygen, glucose and other required building blocks. Byimproving the local perfusion also the beta cells or other glucosesensing element can react without unwanted delays to fast glucosevariations, since the delay of the glucose transport for the bloodsystem to the ISF compartment and to the sensor is reduced when localblood perfusion is increased.

The tissue treatment element, according to some embodiments, is used tostimulate tissue at the delivery site to improve insulin uptake in thebody. In some embodiments, the tissue treatment controller and tissuetreatment element function together to reduce the drug absorption delaysand variations, through a feedback control that may involve the sensorutilized in the drug delivery system of the present invention. Thetissue treatment element may use different methods and devices asdescribed by the present applications to stimulate or inhibit tissue,which may lead to increased blood perfusion that improves insulinabsorption or similarly to reduce insulin absorption when necessary.

Some embodiments of the present invention provide for an implantabledrug delivery device for the automatic and direct introduction of a drugto a target site. The implanted drug delivery device includes tissuetreatment element, as well as controller, delivery member, and anintrinsic drug production compartment. The implanted device may alsoinclude a sensor for the drug level. The implantable device furtherincludes an external, non-implanted user interface that provides theuser with an interface that controls the implanted delivery device. Theuser interface includes functions related to dosage form, dosage timing,and dosage trigger, which more are provided in relation to a database.The user interface may, for example, be provided in the form of a PDA,personal computer, mobile or cellular telephone or the like.

The controller, according to some embodiments, may initiate glucoseproduction and dosage selection based on the sensed glucose levels. Theuser interface may allow a user to determine the timing of glucoseproduction, dosage and delivery time. The controller and sensor functionin a concerted manner to sense and control the level of drug deliveryfor example including but not limited to insulin. Such concertedfunctionality reduces any error to a minimum. the sensor used includes acontinuous glucose monitor that provides continuous reading of the bloodglucose levels. The controller may control the output of the tissuetreatment element based on the sensed data, thereby creating a feedbackloop that is able stabilize the insulin absorption into the bloodsystem.

In some embodiments, the drug is delivered to the target site using adelivery member, for example including but not limited to one or more ofa catheter, a permeable membrane, a selectively permeable membrane, aplurality of catheters, grafted tissue, blood vessel, or the like. Thesensor or tissue treatment element may be incorporated into the deliverymember.

In some embodiments, including also implanted drug delivery devicesembodiments, of the present invention, the tissue treatment element isused to improve, modify and/or stabilizing the pharmacokinetic and/orpharmacodynamic profile of a drug delivered to the target site using adelivery member, for example including but not limited to a catheter,for a drug that is to be absorbed into the blood or lymphatic system.The devices described in some of the embodiments of the presentapplication apply additional treatment or stimulation to the vicinity ofthe drug delivery site. The tissue treatment element may be implanted orplaced externally to stimulate the required region.

In some of the embodiments of the present invention, including alsoimplanted drug delivery devices embodiments, drug delivery may beundertaken with the use of at least one or more catheter, or a permeablemembrane, or a selectively permeable membrane, or the like. At least oneor more catheters may further encase a sensor, tissue treatment element,or other component of the drug delivery device of the present invention.

In some of the embodiments of the present application, including alsoimplanted drug delivery devices embodiments, a sensor may be added forcontrolling the drug delivery. In any one of those embodiments, thesensor may be any state of the art sensor able to monitor and measure ameasurand, for example including but not limited to glucose,cholesterol, hormone, protein, urea, carbohydrate, or the like. thesensor is used in conjunction with a controller to regulate a drugdelivery protocol in response to the sense measurand levels. Anembodiment of the present invention uses a continuous glucose monitor tocontrol insulin levels in the tissue. Some embodiments of the presentinvention are obtained by automatically controlling the insulin infusionrate using a continuous glucose sensor and a control algorithm,effectively producing an artificial pancreas. This provides a closedloop control of glucose and insulin levels that are closely monitoredand controlled to regulate the glucose level and reduce hyperglycemic orhypoglycemic events.

In any of the embodiments of the present invention, any implantedcomponent may be made of biocompatible components. The materialincluding the various components of the drug delivery device are inertand do not react with the implantation site.

In some of the embodiments of the present invention the implantedportion of the device is implanted subcutaneously. Implantation may becarried out in a minimally invasive surgical procedure such as keyholesurgery with local anesthesia. Implantation may be carried out via asubcutaneous injection of the drug delivery device.

In some of the embodiments of the present invention the user interfaceallows the user to operate and communicate with the implanted device.The user interface may be coupled to an external sensor. The userinterface may have an integrated sensor for example including but notlimited to a glucose monitor, cholesterol monitor, or the like.

Communication between the user interface and implanted device may beachieved with one or more of various communication protocols includingbut not limited to wireless, wired, cellular, optical, IR (infrared), RF(radiofrequency), acoustic or the like. The user interface may come inthe form of a personal computer, PDA, cellular telephone orcommunicator, mobile telephone or communicator, or the like. Theinterface provides the user with one or more options to control theimplanted drug delivery device with regard to tissue treatment element,dosage form, dosage timing, and dosage trigger or the like, by accessinga database, allowing the user to control drug delivery parameters.

Some embodiments of the present invention provide a drug delivery devicethat is able to better control the drug absorption cycle reducing to aminimum extreme situations. This is done, according to some embodiments,by way of better control of the drug delivery and/or by improving tissueabsorption of a drug. Specifically, some embodiments enable theforegoing by applying a controllable treatment to the vicinity of thedrug infusion site.

The introduction of a tissue treatment element into a drug deliverydevice has been discussed in various applications by the inventors ofthe instant application. However the method by which the tissuetreatment is carried out may vary widely. Furthermore the type of tissuetreatment employed may include at least one or more of nociceptive axonreflex, heat, cold, intermittent temperature change, ultrasound,optical, massage, physical stimulation, vibration, suction, IR,microwave, RF, optical, infusion of one or more additional substances,or the like. These treatments may be applied on the external skinsurface, in internal tissue, or subcutaneous tissue in order to bringabout an effect.

A tissue treatment protocol may be carried out at the target site or inits vicinity. One tissue treatment protocol may be heating totemperature of about 39.5° C. which is applied for short bursts for aperiod of 2-60 seconds every few minutes, evoking vasodilatation thatimproves the drug pharmacokinetics and/or pharmacodynamics in the druginfused tissue region. However, the specific treatment protocolparameters related to tissue type, threshold levels, burst timing,resting period, heat levels, heating power, time required fortemperature rise and fall, and so forth, are variable and controllable.Some embodiments, whether as systems or methods of the presentinvention, provide for a system and/or method that are customized for anindividual and feature a user specific treatment protocol.

Heat (and the heating process) may be applied to the vicinity of thedrug infused tissue region. In some cases, such as for the infusion ofsome types of insulin and/or other proteins to the tissue heating to atemperature above some limiting level, such as for example 37° C., theheating is applied only to the vicinity of the drug infused tissue andnot to the drug infused tissue region itself. This limitation of theheating area and/or volume prevents heating the drug above a limitingtemperature that can denature or modify the drug itself. Heating thedrug infused region vicinity induces a vasodilatation response also inthe drug infused tissue region as was shown by W. Margerl et. al.,Journal of Physiology, 497.3, pp 837-848 (1996), which discloses thatheating the skin can induce vasodilatation in human at a distance ofeven 30 mm also due to activation of the nociceptive axon reflex. Heatmay be applied according to many methods and devices described hereinand/or in the applications incorporated herein by reference, includingbut not limited to one or more of direct heating through thermal energy,which can be generated electrically, such as using a resistor, orchemically, such as using exothermic reaction, and/or applying otherforms of energy, including but not limited to ultrasound, opticalradiation, electromagnetic radiation, microwave, RF (radio frequency)energy and so forth.

The human neural response to thermal stimulation includes severalmechanisms such as the Nociceptive Axon Reflex that inducevasodilatation among other effects. The neural thermal response may varywidely between individuals. Therefore, in some embodiments, the systemand method of the present invention feature a customized, calibrated,individualized tissue treatment that may be adjusted in one or moreaspects to a specific individual to provide optimal drug delivery for anindividual through the application of optimized tissue treatment.

The neural thermal stimulation protocol may be calibrated for individualpatient to optimize the stimulation protocol according to their ownnociceptive axon reflex activation threshold. For example, W. Margerlet. al. discloses that the vasodilatation evoking temperature after 64seconds of heating can vary between 37-43° C. for different subjects,therefore individualized control of tissue heating may improve theefficiency, the accuracy and/or the repeatability of a drug deliverysystem with the required control of a tissue treatment element.Calibration can be achieved relative to a specific tissue targeted site.They also showed that in some cases short periods of heating can alsoevoke vasodilatation for a period of few minutes. Therefore it may bepossible to control the pharmacokinetic and/or pharmacodynamicproperties of a drug delivered to a tissue region, with the introductionof heat to evoke vasodilatation, eventually leading to improved druguptake. However, heat can also be problematic as it may affect or evendegrade the function of the drug itself. Thus heating for short timeintervals with one to few minutes pause between them may induce lessexcessive heat to the tissue and prevent heating the infused drugitself, in cases heating the drug is unwanted effect, or can reduce thesystem power consumption.

A method for calibrating the treatment device is to initiate tissuestimulation gradually in the first instant of use of the treatmentdevice and measure the treatment effect on the tissue, such asvasodilatation, using a specific sensor, including, for example (but notlimited) a Laser Doppler Flowmetry (LDF) that is connected to theprocessor unit that controls the treatment device. The controller unitdetermines what level of tissue treatment to apply, to optimize thetreatment effect without causing any adverse effects. For example, inthe case where the tissue treatment employed is applying heat having thedesired effect of increasing vasodilatation, the tissue treatmentelement may gradually heat the tissue until a predefined safety limitand measure the local tissue vasodilatation. The level of bloodperfusion and vasodilatation can be measured by Laser Doppler Flowmetry(LDF) or by other sensors accepted or known in the art. Another optionfor measuring the blood perfusion is using an optical sensor formeasuring tissue absorption and/or scattering, for example at thewavelength range of about 700 to about 1000 nm, which relates to thehemoglobin concentration at the probed tissue region. The processingunit may use the sensor information to determine the thresholdtemperature that evokes the neural response which induces the requiredvasodilatation level.

The calibration process may be carried out with an individual todetermine the limits of the vasodilatation neural response and also thelevel of discomfort the individual is willing to endure. The processalso determines the temperature threshold that is safe. For example, thevarious parameters, may include (but not limited to) burst timing,timing and length of resting period, heat levels, temperature, orcurrent type. These parameters may be changed in order to personalizethe treatment protocol relative to the user.

Another method for calibrating the treatment device may be to initiateapplication of tissue stimulation gradually. For example, the first timethat the treatment device is used for an individual, tissue stimulationis applied gradually and then the treatment effect on the tissue ismeasured, by, for example, vasodilatation, using a specific sensor asdescribed above until the required level of induced vasodilatation isachieved or the maximal safety temperature is reached. The processingunit uses this information regarding the baseline for the individuallyadjusted treatment level to determine the future tissue treatment levelsfor that specific patient.

In some embodiments, the controller may have access to various treatmentprotocols and historical data (which may be locally stored in a memoryconnected to the controller) relative to the different situation sensedby at least one or more sensor. The controller may also employ learningalgorithms, including, for example (but not limited to), artificialintelligence methods to adjust or adapt the treatment protocols to bemore specific or tailored to the drug delivery needs and of the user.

In some embodiments, the automated calibration process may be repeatedperiodically, for example every 6-12 hours, to compensate for changesthat might have an influence on the temperature threshold of the neuralthermal response, such as the axon reflex response of the individual.Any of the parameters, including but not limited to one or more of bursttiming, timing and length of resting periods, heat levels, temperatureor current type (for example) may be adjusted accordingly.

In some embodiments, the calibration process is repeated every time (orshortly before) the drug delivery or the tissue treatment element isoperated. For example, the calibration process may be repeated duringinsulin bolus injection to ensure an appropriate induced vasodilatationresponse.

In some embodiments, event related calibration may be used to prevent orreduce the occurrence of gradually appearing variations in the neuralresponse, such as axon reflex, due to variations of factors thatinfluence the neural response, for example including but not limited tolevels of nitric oxide and/or noradrenaline at the target tissue site.

In some embodiments, when tissue treatment, such as heating, is appliedto the treatment area, a treatment parameter, for example temperature,may gradually be adjusted by the device's controller while measuring thedesired tissue parameters such as vasodilatation, which may use LaserDoppler Flowmetry (LDF), to create a feedback calibration loop. Oncevasodilatation reaches an intended value, the amount or rate of tissuetreatment is stabilized to maintain that level of dilatation over aperiod of time.

In some embodiments, the calibration process is repeated also during thetissue treatment or stimulation. In this case, the treatment, such asheating, after initiation as previously described, is then regulated tomaintain the desired tissue parameter(s), such as vasodilatation level,stabilized to a target level, more during the entire treatment.Stabilizing the desired tissue parameter, such as vasodilatation level,stabilizes also the absorption of drug in the blood and improves theconsistency and reproducibility of the pharmacokinetics andpharmacodynamics. Controlling the tissue treatment level according tothe desired tissue parameter(s), such as the vasodilatation level forexample, may also reduce the power consumption of the treatment deviceaccording to some embodiments.

For example, in case of heating, since a short period of heating to acertain temperature above the threshold temperature initiates the axonreflex response and vasodilatation, there may not be a need to keep thetemperature high for a long period, because of the lag effect of theaxon reflex. Reduction of the temperature also reduces powerconsumption.

In some embodiments, calibration processes are repeated also during thetreatment. In such a case, the treatment, such as drug administration,is started. The stimulatory effect is then calibrated with regard to theeffect of drug administration, so that the level of drug (for example)may and be used to calibrate the desired amount of stimulation.

In some embodiments, the neural response that induces vasodilatation isstimulated by applying a mechanical force to the vicinity of the druginfused region, including but not limited to one or more of pressure,massage, vibration, suction and/or other known in the art mechanicalstimulation. These tissue treatments or stimulation are known tostimulate the nociceptive axon reflex as well. Among the advantages ofmechanical stimulation is that mechanical stimulation does not damagethe drug, whereas for example heating above 37° C. might damage insulin.The calibration of the applied mechanical force may be performed byusing one of the procedures described above.

In some embodiments, the neural response that induces vasodilatation maybe additionally stimulated by infusion of one or more additionalsubstances which may include any known peripheral vasodilator, such astolazine, naftidrofuryl or suloctidil, to the vicinity of the druginfused region. In some embodiments, the additional substance infusedinto the vicinity of the measured tissue region modifies the drugpharmacokinetic and/or local blood perfusion with or without thecreation of a chemical or other reaction between the drug and said oneor more substances. This effect may be additive or synergistic to theabove described forms of stimulation. For instance, nitroprusside, whichinduces vasodilatation, can improve blood perfusion in the drug infusedtissue region. Another example is capsaicin that stimulates a neuralresponse through the VRI receptor and produces a similar response tothermal stimulation. The calibration of the level of the appliedadditional one or more substances may be performed by using one of theprocedures described above. In some embodiments, the neural responsethat induces vasodilatation may be additionally stimulated by applyingelectrical current (which is known to increase tissue blood flow) to thevicinity of the drug infused region. The calibration of the level of theapplied electrical current may be performed by using one of theprocedures described above.

In some embodiments, the neural response that induces vasodilatation maybe stimulated through a combination of the above suggested stimulationtypes. For example, by combining low temperature heat (for example below37° C.) and mechanical stimulation, a better neural response may beachieved without damaging the drug molecule because of excessive heat.Another non-limiting example involves combining low temperature heat(for example below 37° C.) and infusion of an additional substance forobtaining a neural response without damaging the drug molecule becauseof excessive heat. Another non-limiting example involves combiningapplication of a low level of thermal stimulation (for example below 37°C.) and application of electrical current to increase tissue bloodperfusion more efficiently, without damaging the drug molecule becauseof excessive heat.

In some embodiments, the induced neural response, such as thenociceptive axon reflex, may also induce widening of the capillary poresand increasing the capillary wall permeability. This effect is alsosignificant for improving the absorption of said drag through thecapillary wall.

In any of the embodiments of the present invention, the tissue treatmentelement may be used to treat a tissue region to which insulin is infusedduring basal or bolus insulin delivery. One possible effect of thetissue treatment is improving the efficiency of absorption of theinsulin into the blood and/or lymphatic systems, thereby reducing theamount of the insulin needed to create the desired metabolic effect.Without being limited by a single hypothesis, the undesired adverseeffects of the excess insulin levels, such as excess weight gain, may bereduced.

Another effect of the tissue treatment according to some embodiments isimproving and reducing the amounts and the duration that the insulinremains at the tissue infused region, since it is absorbed faster in theblood and/or lymphatic systems. Without being limited by a singlehypothesis, the undesired local adverse effects of the excess insulinlevels, such as the lipohypertrophy or local irritation may be reduced.Also, another possible benefit to using the tissue treatment element ofthe present invention is the induced increase in local blood perfusion,which reduces the local inflammation effects seen in current infusionsets. Another possible benefit to treating the tissue target area is thereduction of the short and long term local effects of insulin on theinsulin infusion site, therefore the tissue treatment element may (and))lengthen the duration of using the same delivery site and may increasethe longevity of the functionality of the infusion set.

In some the embodiments of the present invention, the stimulationprotocol, may be determined by the controller, depending on the drugdelivery mode used. For example, tissue stimulation methods may beactivated for a drug delivery protocol of elective or preprogrammedboluses for brief periods to provide a boost to insulin absorption. Insome embodiments, tissue and/or skin treatment methods may form a partof all or some of the elements of complex pre programmed boluses,including but not limited to split wave, square root and other boluspatterns. The stimulation may be activated for the initial phase of astandard bolus protocol, specifically for pre-programmed components of asplit bolus or at intervals of interest of the square bolus. Stimulationmay also be activated by a pre-programmed duty cycle independent of thebolus type. Moreover, the intermittent activation can be synchronizedwith individual bolus delivery components of the basal rate.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The materials, methods, andexamples provided herein are illustrative only and not intended to belimiting.

Although the foregoing has been described with respect to drug deliveryof insulin for the treatment of diabetes, this is a non limiting exampleof the present invention. Any additional chronic or acute condition maybe treated with the drug delivery device of the present invention, forexample including but not limited to hypoxia, anemia, cholesterol,stroke, heart or the like.

Implementation of the method and system of the present inventioninvolves performing or completing certain selected tasks or stepsmanually, automatically, or a combination thereof. Moreover, accordingto actual instrumentation and equipment of preferred embodiments of themethod and system of the present invention, several selected steps couldbe implemented by hardware or by software on any operating system of anyfirmware or a combination thereof. For example, as hardware, selectedsteps of the invention could be implemented as a chip or a circuit. Assoftware, selected steps of the invention could be implemented as aplurality of software instructions being executed by a computer usingany suitable operating system. In any case, selected steps of the methodand system of the invention could be described as being performed by adata processor, such as a computing platform for executing a pluralityof instructions.

Although the present invention is described with regard to a “processingunit” or “computer” or “computer network”, it should be noted that anydevice featuring a data processor and/or the ability to execute one ormore instructions may be described as a computer, including but notlimited to a PC (personal computer), a server, a minicomputer, acellular telephone, a smart phone, a PDA (personal data assistant), apager. Any two or more of such devices in communication with each other,and/or any computer in communication with any other computer, mayinclude a “computer network”.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an exemplary catheter for drug delivery combined witha heating element attached to the skin around the catheter, according tosome embodiments of the present invention.

FIG. 2 illustrates an exemplary catheter for drug delivery combined witha heating element embedded into the catheter tube, according to someembodiments of the present invention.

FIG. 3 illustrates an exemplary catheter for drug delivery combined withelectric wires embedded into the catheter tube, according to someembodiments of the present invention.

FIG. 4 illustrates an exemplary catheter for drug delivery combined withelectric wires attached to the catheter tube, according to someembodiments of the present invention.

FIG. 5 illustrates an exemplary connector between a catheter for drugdelivery and the drug delivery pump, where the connector connects thetube for the drug delivery as well as electric wires, according to someembodiments of the present invention.

FIG. 6 illustrates an exemplary device for treatment of a tissue regioncombined with an infusion catheter made of disposable part and reusablepart, according to some embodiments of the present invention.

FIG. 7 illustrates an exemplary device for treatment of a tissue regioncombined with an infusion catheter made of disposable part and reusablepart, according to some embodiments of the present invention.

FIG. 8 illustrates an exemplary device for treatment of a tissue regioncombined with an infusion catheter made of disposable part and reusablepart, according to some embodiments of the present invention.

FIG. 9 illustrates an exemplary device for treatment of a tissue regioncombined with an infusion catheter made of disposable part and reusablepart, according to some embodiments of the present invention.

FIG. 10 illustrates an exemplary device for treatment of a tissue regioncombined with an infusion catheter and drug delivery pump, according tosome embodiments of the present invention.

FIG. 11 illustrates an exemplary catheter for drug delivery combinedwith a mechanical vibrating element attached to the skin around thecatheter, according to some embodiments of the present invention.

FIG. 12 illustrates an exemplary catheter for drug delivery combinedwith a mechanical vibrating element attached to the skin around thecatheter, according to some embodiments of the present invention.

FIG. 13 illustrates an exemplary catheter for drug delivery combinedwith a massaging element that massages the skin around the catheter,using air cushion controlled by the drug delivery pump, according tosome embodiments of the present invention.

FIG. 14 illustrates an exemplary catheter for drug delivery combinedwith a suction element that affects the skin around the catheter,according to some embodiments of the present invention.

FIG. 15 illustrates an exemplary catheter for drug delivery withadditional pumping element that move the infusion fluid in and out ofthe catheter, according to some embodiments of the present invention.

FIG. 16 illustrates an exemplary catheter for drug delivery withadditional pumping element that move the infusion fluid in and out ofthe catheter, according to some embodiments of the present invention.

FIG. 17 illustrates an exemplary catheter for drug delivery with anacoustic excitation of the skin close to the catheter, according to someembodiments of the present invention.

FIG. 18 illustrates an exemplary catheter for drug delivery combinedwith an optical radiation source irradiating the skin close to thecatheter, according to some embodiments of the present invention.

FIG. 19 illustrates an exemplary catheter for drug delivery combinedwith an optical radiation source irradiating the skin close to thecatheter, according to some embodiments of the present invention.

FIG. 20 illustrates an exemplary double lumen catheter for drugdelivery, according to some embodiments of the present invention.

FIG. 21 illustrates an exemplary catheter for drug delivery combinedwith a port for syringe insertion, according to some embodiments of thepresent invention.

FIG. 22 illustrates an exemplary device for excitation of the skin and atissue region underneath to which a drug is injected, according to someembodiments of the present invention.

FIG. 23 illustrates an exemplary device for improving insulinpharmacodynamics, according to some embodiments of the presentinvention.

FIG. 24 illustrates an infusion catheter for insulin delivery with Ushaped heater, according to some embodiments of the present invention

FIG. 25 illustrates an infusion catheter for insulin delivery withcircular thin heater, according to some embodiments of the presentinvention

FIG. 26 a illustrates an example of a graph of the insulin effect withand without treatment, according to some embodiments of the presentinvention.

FIG. 26 b illustrates an example of a graph of the insulinpharmacokinetics with and without treatment, according to someembodiments of the present invention.

FIG. 27 schematically describes a catheter for drug delivery combinedwith a radiation element attached to the skin around the catheter.

FIG. 28 schematically describes a catheter for drug delivery combinedwith a radiation source that guides the light through the catheter tube.

FIG. 29 schematically describes a drug delivery device combined with aradiation source that guides the light through the catheter tube.

FIG. 30 schematically describes a drug delivery device combined with aradiation source that guides the light through the catheter tube.

FIG. 31 schematically describes a drug delivery device combined with aradiation source that guides the light through the catheter tube.

FIG. 32 schematically describes a catheter for drug delivery combinedwith a radiation source that guides the light through the catheter tube.

FIG. 33 schematically describes a catheter for drug delivery combinedwith a radiation source that guides the light through the catheter tube.

FIG. 34 schematically describes a catheter for drug delivery combinedwith a radiation source that guides the light through the catheter tube.

FIG. 35 schematically describes a catheter for drug delivery combinedwith a radiation source that guides the light through the catheter tube.

FIG. 36 schematically describes a catheter for drug delivery combinedwith a radiation source that guides the light through the catheter tube.

FIG. 37 schematically describes a catheter for drug delivery combinedwith a radiation source that guides the light through the catheter tubeand with an optical sensor.

FIG. 38 illustrates an exemplary implanted drug delivery device combinedwith a heating element, according to some embodiments of the presentinvention.

FIG. 39 illustrates an exemplary implanted drug delivery device combinedwith a heating element attached to the skin above the drug infusedregion, according to some embodiments of the present invention.

FIGS. 40A-D are schematic block diagrams of embodiments of the implanteddrug delivery device according to the present invention.

FIGS. 41A-D are schematic diagrams of an exemplary embodiment of theimplanted drug delivery device, of FIGS. 40A-D, according to the presentinvention.

FIG. 42 is a flow chart of another exemplary method according to presentinvention.

FIG. 43A is a schematic block diagram of an exemplary embodiment of theimplanted drug delivery device according to the present invention.

FIG. 43B is a schematic diagram of an exemplary embodiment of theimplanted drug delivery device according to the present invention.

FIGS. 44A-C are various schematic diagrams of exemplary embodiments ofthe implanted drug delivery device according to the present invention.

FIG. 45 is a schematic block diagram of a drug delivery device used withthe treatment method of the present invention.

FIG. 46 is a flow chart of the treatment calibration process accordingto the present invention.

FIG. 47 is a flow chart of the treatment calibration process accordingto the present invention.

FIG. 48 illustrates an exemplary drug delivery device, wherein the firstdevice or the first part is an indwelling catheter of an infusion pumpinserted to the tissue or to a blood vessel, according to someembodiments of the present invention.

FIG. 49 illustrates an exemplary drug delivery device, wherein anattachment to the skin includes a power source, exciting source,adhesive to the skin and matching layer between the exciting source andthe skin, according to some embodiments of the present invention.

FIG. 50 is a flow chart illustrating an exemplary method for controllingtemperature of heating that is provided by a treatment element in orderto prevent degradation of a temperature sensitive drug.

DETAILED DESCRIPTION OF THE INVENTION Method and System for DrugDelivery

The present invention relates to devices for improving, modifying and/orstabilizing pharmacokinetic and/or pharmacodynamic profile of a druginfused into the tissue by a catheter and absorbed into the blood orlymphatic system. The devices described in some of the embodiments ofthe present application apply additional treatment or stimulation to thevicinity of the drug delivery site. The treatment can be one orcombination of the following tissue treatment treatments modalities:heating, modifying temperature, massaging, mechanical vibration,acoustic vibration, ultrasound, suction, infusion of an additionalsubstance or chemical, applying a low electric field, applying a lowmagnetic field, light irradiation, infrared (“RF”) irradiation,microwave (“MW”) irradiation, etc. In some embodiments, the device has acatheter for insertion within the tissue to infuse a substance into theinfused tissue region. The infused tissue region (i.e., the infusedregion) can be one of the skin layers or the subcutaneous tissue ordeeper tissue elements within any organ or viscera.

The catheter may also have a securing mechanical part that adheres tothe skin and secures the catheter into its location and prevent it frombeing pulled out accidentally. The proximal end of the catheter may beconnected to a drug delivery device which controls the infusion profileof the drug. In some embodiments, the drug delivery device also controlsthe additional treatment applied to the infused tissue region. In thoseembodiments, there is a communication channel between the drug deliverydevice and the treatment device. The communication can be either wiredor wireless. Portions of the treatment device can be disposed inside thedrug delivery device or outside of it. In some embodiments, the drugdelivery device is a drug delivery pump, such as an insulin pump.

In some embodiments, the present invention is a device controlled by apump that infuses a drug into a tissue region, which applies anadditional treatment to the vicinity of the drug delivery site. In someembodiments, the pump's electronic processing unit operates based on apredetermined protocol or algorithm, any additional inputs and/or adrug-infusion profile of the applied treatment. In some embodiments, thepump's electronic processing unit communicates with the treatment deviceprocessing unit, which operates based on a predetermined protocol oralgorithm and according to a drug infusion profile of the appliedtreatment. In some embodiments, the device regularly queries the pump'sstatus using the pump's built-in communication capability. Based on thereceived data, the device operates in accordance with a predeterminedprotocol or algorithm of the applied treatment.

In some embodiments, the devices are neither controlled by the pump norhave any communications with the drug delivery pump. Instead, thedevices detect the drug-delivery profile through the catheter and applythe treatment according to a predetermined protocol or algorithm. Insuch embodiments, the treatment device includes a sensor that can detectthe drug infusion flow inside the catheter and deliver the informationto the device processing unit, which operates based on a predeterminedprotocol or algorithm and on an infusion profile of the appliedtreatment. The drug flow can be detected by any conventional sensors,such as an optical sensor that detects the drug flow in a transparentcatheter, a laser Doppler sensor, an ultrasonic Doppler sensor, apressure sensor, a conductivity sensor, an inductance sensor that canmeasure changes in the flow rate of the infusion fluid under inducedmagnetic field. In some embodiments, the drug flow sensor detects notonly the existence of a drug infusion flow, but also the infusion rateand uses that information in the treatment algorithm. In someembodiments, the drug infusion sensor detects the electromagnetic oracoustic emission of the drug delivery pump motor or electronics. Insome embodiments, the device senses some additional parameters of thetissue and uses that information as well in the treatment algorithm.

In some embodiments, tissue treatment controls the temperature of thetissue region into which the drug is delivered. In some embodiments,temperature control can be to set a profile of temperature rise in aknown rate, temperature stabilization at a known period and ending theprofile by returning to the natural tissue temperature. This profile canbe induced by a heater that heats the drug infused tissue region. Othertemperature profiles for treatment or excitation of the drug infusedtissue region are possible as well. For example, a cooling profile fordecreasing blood perfusion or to induce a specific pharmacokineticand/or pharmacodynamic profile for the drug or heating for short timeintervals to further improve drug pharmacokinetics or pharmacodynamics.In some embodiments, the temperature profile can be applied to a largerregion than the drug infused tissue region. Doing so may improve bloodperfusion also in the vicinity of the drug infused tissue region and byway of a further increase drug absorption rate into the circulation byincreasing the available absorption volume. In some embodiments, thetemperature profile can be applied to a region smaller than the druginfused tissue region to save battery life.

A device for heating the tissue region into which the drug is deliveredaccording to some embodiments of the present invention is illustrated inFIG. 1. In this embodiment, the infusion catheter is combined with aheating element attached to the skin around the catheter. The treatmentdevice is a flat circular structure 7 with an opening in its center forthe catheter tube 5 for entering the subcutaneous tissue. The other endof the catheter is connected to the drug delivery pump. In theillustrated embodiments, the treatment device includes a heating element2, which may include a printed circuit board having the heating elements(e.g., resistors) provided thereon (as can be understood by one skilledin the art, other heating element types may be used). In someembodiments, the printed circuit board includes a temperature sensor 3.In some embodiments, a cooling element may be included in the case wheremore demanding temperature profiles are used.

The heating element can include a controller that controls the heatingelement (e.g., on/off or increased/decreased power) in order tostabilize the skin temperature to the required temperature according tothe algorithm. In some embodiments, the temperature can be between32-40° C. in order not to irritate the skin on the one hand and to havea sufficient effect on the tissue on the other hand. Temperaturestabilization algorithms are well know in the art and can be executed byrelatively simple controllers/processing units or ASICs. Skin or tissuedamage depends on the applied temperature and the heat exposure time, sofor a short period of few minutes even higher temperatures up to rangeof 42° C. can be used.

In some cases lower heating temperatures may be required. For instance,Novolog (aspart) insulin can be exposed to maximal limiting temperatureof 37° C. (FDA document NDA 20-986/S-024, “NovoLog Insulin aspart (rDNA)Injection”, Jul. 26, 2004). In such an embodiment, the skin temperaturecan be slightly higher as long as the immediate vicinity of the insulininfusion site is below 37° C. For this case, there is advantage in theheating configuration by the present invention and shown in FIG. 1,since the device warms the tissue and not the insulin, so minimaltemperature modification is affecting the injected insulin per se whilemaximal heat stimulation is applied to the tissue, in order to increaselocal blood perfusion. Also as shown in FIG. 1, the heating element 2 isnot in contact with insulin infusion catheter 5. For this reason, thepresent invention suggests also thermal isolation 7 between insulincatheter 5 and heating element 2, such that the insulin is notoverheated and minimally exposed to high temperatures.

In some embodiments, an additional or alternate temperature sensor 4 islocated inside the catheter tube 5. This temperature sensor allowsbetter control of the temperature of the drug infused tissue region.Specifically, first, the insulin limiting temperature inside the tissuecan be avoided even though higher temperatures can be used at the skinto get optimal stimulation of the blood perfusion in the region. Also,by regulating the temperature inside the drug infused region to a fixedoptimal temperature, a better stabilization of the drug chemicalprocesses, pharmacokinetics, absorption into the blood system and/orpharmacodynamics can be achieved. The local temperature variations inthe drug infused region induced by ambient temperature variations aswell as other factors induce variations in the blood absorption rate ofthe drug and induces larger variability of the drug pharmacokinetics andpharmacodynamics. As mentioned before, in the case of insulin delivery,it is important to reduce the variability of the temporal profile of theinsulin absorption into the blood and tighter local temperature controlcan be advantageous improve the glucose level regulation of diabeticpatients.

In some embodiments, the heating element 2 and one or two of thetemperature sensors 3 and 4 are connected to the drug delivery pumpthrough cable 6. In this embodiment, the drug delivery pump may includethe power source and the controller of the treatment process.

In some embodiments, element 7 covering heating element 2 is thermallyisolating. Specifically, element 7 reduces the heat dissipation to theenvironment in case of heating the tissue. As mentioned earlier, element7 can also thermally isolate the drug in catheter 5 from being exposedto the increased temperature of the heater(s). In case of cooling of thedrug infused tissue region, element 7 reduces heat transfer from theenvironment to the cooled tissue region. It can also ease the thermalstabilization of the infused tissue region, in case of changingenvironments and ambient temperatures.

In some embodiments, the heating device as shown in FIG. 1 is attachedto the tissue with an adhesive layer (tape) 1. The adhesive layer canalso cover the heating element. In some embodiments, the adhesive layermay be a thermal conducting adhesive or a thin adhesive layer. Theadhesive layer may be provided covered with a laminate (not shown inFIG. 1) that is peeled off by the user before insertion of the catheterand attachment of the heating device. Typically, for catheter insertion,the device is supplied with a sterile needle inside the catheter (notshown in the figure) that is pulled out after insertion of the catheterto the required tissue region.

In some embodiments, the heating device shown in FIG. 1 includes anadhesive thermally conducting layer in contact with the skin, anelectrically isolating layer with temperature sensors, a heating layer,a thermally isolating layer and an adhesive layer for attaching heatingdevice 2 to additional thermal isolation 7 if needed. All layers can bemanufactured using printing techniques and mass production methods.

Another device for heating the tissue region into which the drug isdelivered is illustrated in FIG. 2. In this embodiment, the infusioncatheter contains a heating element 52 in a distal part 50, which isclose to the infused tissue region. The heating element can be made of aconductive wire with high enough resistance and good strength anddurability. For instance, tungsten wires or deposition of thin copperstrip are commonly used for this purpose. Heating element 52 may beembedded into the catheter tube during the manufacturing of the tube,using methods known in the art. For example, this can be done bywrapping the wire coil on a thin wall tube and then covering it with asecond polymeric layer. The other side of the heating wire coil 51 isdirected up in the tube as well. In some embodiments, the heating wirecan be shaped in other forms such as a single loop or zigzag or whatevercan be efficiently manufactured to provide the required heat for theinfused tissue region. An advantage of heating inside the tissue is asmaller volume of tissue around the drug infused region is heated andhence requires less electric power. Also, the heated volume, usually inthe subcutaneous tissue, is better isolated from the skin temperaturewhich may vary with the ambient temperature. However, in this case, thecatheter temperature can be limited to a temperature that will not alterthe properties of the infused drug in case of drugs that are moresensitive to temperature increase then insulin. In the external heatingconfiguration shown in FIG. 1, the spatial temperature distribution maybe such that the skin temperature and tissue regions around but notclose to the catheter tip are at higher temperature without causing anydamage to temperature sensitive drugs. In the external heatingconfiguration, the drug exposure to the higher temperatures may be morelimited, although the high temperature still affects a portion of thedrug infused tissue region or the tissue regions around the drug infusedtissue regions.

In some embodiments, temperature sensor 53 is located inside thecatheter tube as well. This sensor monitors the infused tissue regiontemperature. This temperature sensor allows better control of thetemperature of the infused tissue region. By better stabilization of thedrug chemical breakdown and dissolution processes or pharmacokinetics orabsorption kinetics into the blood system an improved and morereproducible pharmacodynamic profile can be achieved. In this device,the controller can be either in the treatment device or in the drugdelivery pump and controls the heating current to stabilize the infusedtissue region temperature to the required temperatures and durationsaccording to the algorithm.

In some embodiments, device element 56 that supports the catheterattachment to the body is thermally isolating to further reduce thepower requirements of the heating element and by thus, battery weight.The heating device as shown in FIG. 2, is attached to the tissue withadhesive layer 55. The adhesive layer can come covered with a laminate(not shown in FIG. 2) that is peeled off by the user before insertion ofthe catheter and attachment of the heating device. In some embodiments,another temperature sensor 54 may be in contact with the skin to improvethe temperature stabilization algorithm. In some embodiments, only skintemperature is used in conjunction with the catheter heating element. Insome embodiments, heating elements provided internally and externally ofthe tissue may be used.

The other side of the catheter is connected to the drug delivery pump.In some embodiments, in this configuration as well as in otherconfigurations detailed in the subject disclosure, all wires thatconnect the treatment device and the drug delivery pump may be embeddedin the catheter tube connected to pump as shown in the tube crosssection at FIG. 3. In some embodiments, the wires are attached to theouter side of the tube as shown in the cross-section illustrated in FIG.4. Embedding or attaching the wires to the tube enables the device to bemore comfortable for the user (e.g., to be worn and handled).

The wires shown in FIGS. 3 and 4 are preferable connected to the drugdelivery pump. In some embodiments, two connectors may be used forconnection of the disposable catheter and treatment device to the drugdelivery pump. The first connector connects the catheter tube to thepump as currently established, for instance, in many current commercialinsulin pumps. A second connector may be used to connect the wires usedby the treatment device for communication between the pump unit and thetreatment device unit or power supply or connecting sensors used forsensing of tissue parameters and/or infusion parameters to the pumpunit. The wire connector can be one of the known connectors forconnecting electrical wires. In case of using two separate connectorsfor the electrical wires and the infusion tube, the wires can also beseparated from the tube.

In some embodiments, as shown in FIG. 5, the tube connector 102 and theelectrical wires connectors 103-106 can be combined into a singlehousing 101. The single connector housing option is more comfortable forthe user to handle, i.e., to assemble and disassemble the catheter andthe treatment device from the pump unit. The connector housing can alsoinclude a known prior art clip or locking mechanism that enablesdisconnection of the connector only when the locking mechanism ispressed or opened. Such locking mechanism can reduce also the chance ofleakage of the infusion fluid from the connector.

In FIG. 5, four wires are used for controlling the treatment device bythe pump unit and for connecting a sensor that measures the treatmentlevel or effect in order to stabilize the treatment effect to therequired level. In other cases of treatments, sensors and deviceconfigurations, a different number of wires may be connected through theconnector.

In some embodiments, a similar connector can also be used on thetreatment device's side. These embodiments may be more comfortable forthe user in case of an infusion catheter and a drug delivery pump usedfor longer periods such as 2-3 days. For some time periods, the drugdelivery pump can be detached from the user's body leaving a minimalweight and length of tubing in contact with the user's body. Theseembodiments can be useful and more comfortable for taking a shower. Insuch a case, the tubing and wires can include either a connector on bothends, a connector on the treatment device end only or a connector on thedrug delivery pump device end only. In case of having a connector on thetreatment device side, another alternative includes having a disposabletube connecting the treatment device and the drug delivery pump, where areusable electrical cable is attached to the drug delivery pump andincludes a connector for connecting to the treatment device. In someembodiments, the tube and wires may be disposable as with the catheteror its securing device, for instance, as the tube and catheter of commoninsulin infusion sets are designed.

In some embodiments, the treatment device can be made of two parts, onebeing disposable and one being reusable, as shown in FIG. 6. Thedisposable part includes the catheter 150 that is inserted into thetissue and the insertion mechanism (not shown in the figure). In someembodiments, the treatment device can also include the skin attachmentpart 151 and an adaptor mechanism 152 to connect the two parts. In someembodiments, the treatment device can include all or a portion of thetreatment element such as the heating element (in the case of heattreatment or other elements for other tissue treatments or excitationmethods of the present invention). In some embodiments, the treatmentdevice may include one or more sensors.

The reusable part 155 may include all or a portion of the treatmentelement. It may include a processing unit, one or more sensors and apower source. The power source can be a rechargeable battery. As shownin FIG. 6, two parts are attached with a mechanical locking mechanism153 and four pins 154 for electrical connections. In case ofrechargeable battery, the user may have two alternating reusable units155 whereas one is attached to the treatment device and one stayscharging. When the battery in the treatment device is empty, damaged orthe user is instructed (based on a specific battery schedule), the userswitches between the two reusable units. The charger unit has the samemechanical and electrical connection as the disposable part 152 thateasily fits the reusable unit 155.

In some embodiments, the reusable part communicates via a communicationchannel with the drug delivery pump, using wired, wireless, wireline orany other connection. In some embodiments, the treatment device has nocommunication with the drug delivery pump. For example, only thecatheter tube, which is not shown in the FIG. 6, can be connected to thedrug delivery pump.

Consequently, in the case of an insulin pump, this device can be usedwith many of the continuous subcutaneous insulin infusion pumpspresently on the market and for those in development, for similarpurposes. The treatment device identifies by itself the infusion of aninsulin bolus and starts the treatment protocol accordingly. Thebeginning of insulin infusion can be identified as described earlier bya sensor in the treatment device such as an optical sensor on thetransparent tube, a laser Doppler sensor, an ultrasonic Doppler sensor,a pressure sensor connected to the tube, or a conductivity sensor in thetube, under applied magnetic field, or a temperature sensor of theinfusion fluid in the tube. Alternatively, the treatment device canidentify the pump motor electromagnetic emission or acoustic emission todetect the bolus period. The sensors that require contact with theinfusion fluid, such as the conductivity sensor, are located in thedisposable part 152. The other sensors may be either in the disposablepart or in the reusable part with a respective known in the artmechanical structure that allow them to measure the required infusionfluid parameter or parameters.

In some embodiments, a separate unit which is attached to the insulinpump detects the delivery of an insulin bolus and transmits theinformation to the treatment unit to start treatment, either with wiredor wireless communication. The separate unit may sense theelectromagnetic or acoustic emission of the pump motor or read the pumpbuttons when pressed or read the pump display or pump other indicatorsor have an additional button disposed on the pump for manual operationof the tissue treatment device. In some embodiments, the reusable unitmay have at least one user input (e.g., a button) for the user to use(e.g., press) when the user desires the treatment to start.

In some embodiments, the reusable part or the disposable part isconnected with an electrical cable to a third unit that may include thepower source, the control unit or other electronic parts of the device.In some embodiments, a single part disposable treatment device iselectrically connected to the third unit.

An alternate embodiment of the present invention is illustrated in FIG.7, where the reusable part is shaped as a thin disk 160 inserted betweenthe disposable part 163 and the skin. Thin disk 160 can be a heater witha temperature sensor used to aid in stabilizing the temperature of theskin around the catheter insertion area. In some embodiments, thetemperature sensor can be part of a thermostat that automaticallyregulates the heating temperature by connecting and disconnecting theheater element power lines, or other self regulating heaters, such asPTC thermistors, and or increasing or decreasing the power supplied tothe heater.

In some embodiments, the thin heater can be manufactured by printingtechnologies. In some embodiments, the thin heater can be of thicknessof 0.1-0.5 mm. In some embodiments, a thicker heater with thickness of0.5-2 mm may be used. Also, a thin disk can be more flexible and morecomfortable for the user. Before insertion into the tissue, the reusabledisk 160 can be adhered or attached to the disposable part 163 such thatthe treatment element of the reusable device is adhered to the skinabove the drug infused tissue region. In some embodiments, a specialmechanical jig is used for attaching reusable disk 160 to disposablepart 163. In some embodiments, an inserter, such as inserters used forinsulin infusion sets, is used for entering both units to the tissue.The thin heater disk 160 and the catheter securing element 163 can bedisposable. In some embodiments, thin heater disk 160 can fit severalconventional catheter securing elements, including insulin conventionalinfusion sets.

The reusable treatment disk is connected to the drug delivery pump or toa third unit using a cable 162. The reusable treatment disk can performmany treatments or stimulations discussed in the present application,such as heating, massaging, vibrating, acoustic excitation, opticalradiation, RF radiation, MW radiation, applying electrical field etc. Insome embodiments, disposable part 163 can be wider than reusable part160 such that the rims of the disposable part are used for attaching orsecuring the treatment device to the skin.

FIG. 8 illustrates an alternate embodiment in which the disposable part173 includes only the catheter tube 172, the insertion mechanism and theskin adhering element 170. Before insertion of the catheter into thetissue, the disposable part 173 can be attached to the reusable part 177such that treatment elements 174 and 175 of the reusable part gets incontact with the skin when the treatment device is attached to theuser's skin. In some embodiments, the disposable part 173 can beattached to the reusable part 177 with a locking mechanism 176. Thereusable part 177 can be wired or wirelessly connected to the drugdelivery pump or a third unit. Alternatively, it may not be connected tothe drug delivery pump and thus, may include a power source, asdescribed above. The reusable treatment part can perform treatmentsdiscussed above.

FIG. 9 illustrates another embodiment in which the disposable part 752includes the catheter tube 751, the insertion mechanism, the skinadhering element 750 the drug container and passive parts of the drugpump. In this embodiment, the reusable part includes a processing unit,a pump motor and may include some of the sensors, as described in shownin FIG. 6. The power source can be either in the reusable part or thedisposable part. In case of using a rechargeable battery, the batterycan be located in the reusable part, as discussed in FIG. 6. In someembodiments, the disposable battery is located in the disposable unit.Prior to insertion of the catheter into the tissue, the disposable part752 may be attached to the reusable part 753 such that schematicelectrical connection pins 754 fit the disposable part electricalconnection pins and such that mechanical pump operating mechanism 757 inthe reusable part fits the passive parts of the drug pump in thedisposable unit. The pump mechanism can be one of the many known in theart pumping mechanisms. For instance, in case of a peristaltic pump, themechanical pump operating mechanism 757 in the reusable part can be partof the pressure wheel of the peristaltic pump that presses a tube in thedisposable part.

Alternately, a mechanical pump operating mechanism 757 in the reusablepart can be a cog-wheel that rotates a matching pump cog wheel in thedisposable part or moves a linear slider, such that the disposable unitincludes only low cost parts. In some embodiments, some of the moreexpensive parts of the drug delivery pump can be included in thereusable unit. In some embodiments, the disposable part 752 is attachedto the reusable part 753 with a locking mechanism 756. The reusable part753 can be wirelessly or wired connected to the drug delivery pump or toa third unit or not connected and contain the power source as describedbefore. The reusable treatment part can perform treatments discussedabove.

FIG. 10 illustrates an embodiment of the present invention, in whichthere is a single disposable unit 702 including the drug delivery pump,the treatment device, the catheter tube 701, the insertion mechanism,the skin adhering element 700 and the power source. The single unit pumpand treatment device can perform the above described treatments. In someembodiments, in case of a single unit with a heat treatment that can beaccomplished either by direct heating or by indirect heating such as abyproduct of radiation, the drug reservoir is thermally insulated fromthe heating element or from the heated regions. This is useful in thecase of the insulin delivery because of insulin's sensitivity to hightemperatures. In some embodiments, the drug reservoir has in also atemperature sensor to verify that the drug temperature is not exceedingthe limiting temperature. The same thermal insulation of the drugreservoir can be used in embodiments described above with reference toFIGS. 6-9.

The devices schematically shown in FIGS. 6-10 are examples of differentcombinations of disposable and reusable units that provide insulindelivery with treatment or excitation of the drug infused tissue region.As can be understood by one skilled in the art, other embodimentsranging from fully disposable units to fully reusable units (except thecatheter that normally will be disposable) are also possible whereaseach of the device components can be provided in the disposable orreusable units according to its way of implementation and its productioncost.

In some embodiments, the third unit can be attached externally to thedrug delivery device to improve user's comfort. In such a case,electrical wires can be attached to the catheter tube at a large portionof the catheter length and be separated only near the drug deliverydevice such that the drug catheter is connected to the drug deliverydevice and the wires are connected to the third unit. The third unit caninclude also power source and controller. When the drug delivery starts(e.g., drug bolus delivery), the third unit can detect operation of thedrug-delivery device either actively by direct communication between thetwo units or by passively sensing some signals induced by drug deliverydevice when operated as described before, such as using theelectromagnetic emission of the drug delivery device. In someembodiments, the third unit can be disposed in a bag, a pouch, a case,or a belt adaptor containing the drug delivery pump such as devices usedfor carrying insulin pumps. In such a case, the tube is connected to theinsulin pump, while the wires are connected to the carrying device. Thecarrying device can also include a switch for manual start of thetreatment or indicators for indicating that the treatment is applied orindicators that the battery power is adequate, too low or indicatorsthat a problem occurred with the treatment, such as wire disconnection,etc. The switch or indicators, or a portion thereof, can be disposedalso on the reusable unit or disposable unit or on the drug deliverypump.

In some embodiments, the devices by the present invention can have shortrange RF or IR communication with a data management and control unit,such as a Personal Digital Assistant (“PDA”) computer, to a personalcellular phone or to an application specific data managing device thatsupports managing drug therapy. In case of insulin delivery, a datamanaging device can obtain glucose readings either from a glucose sensormanually, through data communication or by reading glucose sensingstrips. The data managing device can get the information aboutpreviously consumed carbohydrates and other food or drinks. The datamanaging device can also retain patient history and relevant parameters,such as weight, BMI, insulin resistance etc.

The data managing device can also calculate the optimal required amountof insulin and the optimal tissue treatment or excitation profile. Thisinformation can be sent wirelessly to the drug delivery pump and to thetreatment device, for optimal drug delivery. The treatment device maytransmit tissue parameters measured by sensors disposed thereon to thedata management unit (which may also be or include the control unit;“data management and control unit”) as additional information for thetherapy calculation or history for future statistics and data analysis.In some embodiments, the data management and control unit may onlyrecommend to the user an optimal drug dosage, an optimal treatmentand/or an excitation profile to be applied to the infused tissue regionand the patient can approve the treatment before it starts. In someembodiments, the data management and control unit may recommend the useran optimal drug dosage only and the patient may approve the dosagebefore it starts and decide on best treatment or excitation to beapplied to the infused tissue region. In some embodiments, the datamanagement and control unit can be part of the drug delivery pump. Insome embodiments, the data management and control unit can include aswitch for manual start of the treatment, indicators for indicating thatthe treatment is applied, indicators that the battery power is adequate,too low or indicators for determining if a problem occurred with thetreatment, such as wire disconnection, etc.

In some embodiments, tissue treatment or stimulation can include (eitheralone or in combination with other stimulation) vibrating the tissueregion into which the drug is delivered. Two examples of such treatmentsdevices are shown in FIGS. 11-12. The vibrating treatment device withopen cover, shown in FIG. 11, includes an electric motor 202 thatrotates a disk 201 with asymmetric load. Rotating this disk causes thetreatment device to vibrate in a circular vibration mode. By adheringthe treatment device to the skin with an adhesive layer, the treatmentdevice vibrates the tissue underneath the treatment device and thecatheter tip. This vibration can have a frequency of about 1-50 Hz,which is commonly used for massaging tissue, an typically includes60-300 rpm. As can be understood by one skilled in the art, otherfrequencies, or rotational velocities can be used as well. In someembodiments, the motor axis can be horizontal with the rotating diskvertical to the skin surface. In this case, the vibrations are verticalto the skin surface in addition to horizontal.

The vibrating treatment device with open cover, as shown in FIG. 12,includes an electromagnet 251 that pulls a ferromagnetic rod with twoweights at either end thereof. A spring returns the rod to his initiallocation after the electromagnet is turned off. Thus, by applying aperiodical signal to the electromagnet, the rod with its weights willvibrate at the periodic signal frequency and induce vibrations to thetissue underneath. To improve vibration efficiency, the rod, weightsmass and the spring force can be designed to have a mechanical resonancefrequency at the required frequency for massaging the infused tissue.

When the resonance frequency is applied to the electromagnet a largeramplitude vibrations is induced. By adhering the treatment device to theskin with an adhesive layer, the treatment device vibrates the tissueunderneath the treatment device and the catheter tip. In someembodiments, the vibration axis can be designed to vibrate to otherdirections, such as vertical or perpendicular to the skin surface. Insome embodiments, the vibration device can vibrate mainly the cathetertip either horizontally or vertically using vibration mechanisms thatinduce excitation of the tissue near the catheter tip.

An alternate embodiment of tissue massaging is illustrated in FIG. 13.This embodiment can massage with lower frequency and larger amplitude ascompared to the vibrating embodiments. The treatment device (which inthis embodiment may be disposable) includes a catheter tip 351 forinserting into tissue (as before), located in the middle of a chamber354 with rigid wall all around except of the skin side, which alsoincludes a flexible membrane 350. The flexible membrane is adhered tothe skin as before with an adhesive layer, as part of the catheterinsertion process described before, to secure the catheter in itsposition. Chamber 354 may be connected with additional tube 353 to thedrug delivery pump 352. The tissue massaging is established by pumpingair in and out of chamber 354 through tube 353 via an additional pump inthe drug delivery pump unit, according to a treatment or massagingprotocol. In this case, the control of the treatment protocol isaccomplished by the drug delivery pump unit and the disposable unit canbe relatively simple and low cost. When the air is pumped out of chamber354, flexible membrane 350 curves into the chamber pulling the tissueadhered to it. When the air is pumped into the chamber, the flexiblemembrane curves out and pushes the tissue. This process is doneperiodically according to a typical frequency of about 0.01-10 Hz. Otherfrequencies are possible as well. In some embodiments, the chamber isfilled with an incompressible fluid, such as water, and appropriate pumpcause the fluid to flow in and out.

In an alternate embodiment, the flexible membrane can include a rigidsurface which includes a plurality of openings and a flexible membranecovering the openings to improve adhesion to the skin, and to spatiallymodulate the skin massage. In yet another alternate embodiment, theflexible membrane outer surface can have small features (bumps)extending out of the surface to improve massaging effect to the tissue.In some embodiments, tube 353 can be connected to a third unit thatcontrols and applies the massage treatment as described before.

Another embodiment of a treatment device is a suction device thatprovides suction of the tissue around the infusion catheter, as shown inFIG. 14. Suction of a tissue region is known to improve blood perfusionin that tissue region. The treatment device (which is disposable)includes a catheter tip 401 for insertion into the tissue (as before),located in the middle of a chamber 404 with rigid wall all around exceptof the skin side, where an opening is included. The chamber walls areadhered to the skin with a circular adhesive layer 400 that seals thechamber rim to the skin. The adhesive layer is attached to the skinduring the catheter-insertion process to secure the catheter in itsposition. Chamber 404 is connected with an additional tube 403 to thedrug delivery pump 402. The skin suction is accomplished by pumping theair out of chamber 404 through tube 403 via an additional pump providedin the drug delivery pump unit. In this case, the control of thetreatment protocol is accomplished by the drug delivery pump unit andthe disposable unit can be made simple and low cost. The suction is doneaccording to a predetermined treatment protocol, for example—a suctionof 1 minute in duration can be applied after an insulin bolus injectionto improve insulin absorption into the blood system. Another example isapplying vacuum in chamber 404 for 30 seconds and then releasing thevacuum for additional 30 seconds. This process can be repeated severaltimes in order to increase blood perfusion in the tissue regionunderneath the treatment device. In some embodiments, the chamberopening to the tissue can be made of a rigid surface with few openingsto increase adhesion area to the skin and to spatially modulate the skinsuction. In some embodiments, tube 403 can be connected to a third unitthat controls and applies the suction treatment as described before.

In some embodiments, in order to modify the delivered-drug'spharmacokinetic and/or pharmacodynamic profile, a small modulation ofthe infusion process through the infusion catheter is induced. In otherwords, the infusion fluid is slightly pulled in and out of the tissueduring or after the drug infusion process. This action induces anincreased flow of interstitial fluid (“ISF”) around the catheter tipbecause of the variable induced pressure fields. The increased ISF flowincreases the drug diffusion distance and reduces the time constant ofthe drug absorption into the blood system. The flow modulation can bedone by the drug delivery pump by reversing the pump direction for shortperiods and small amount of pumped fluids. Also, the drug delivery pumpcan keep moving the infusion fluid in the catheter slightly in and outafter the end of drug bolus infusion.

FIGS. 15-16 illustrate two exemplary embodiments of methods to implementthe above tissue treatment as an additive component to existing drugdelivery pumps, without reversing the drug delivery pump direction.These embodiments include modulating the flow of the infusion fluid inthe infusion catheter tube by two different modalities. In FIG. 15, awheel 503 is provided having its rotating axis off the wheel center.Thus, when the axis is rotating, one side of the wheel applies pressureto the proximal side of catheter tube 501 and pushes the infusion fluidforward. The other side of the wheel 503 releases the catheter tube 501and retracts the infusion fluid a slightly backwards. In FIG. 16, thefluid modulation is done by a piston 553 connected to the catheter tube551 and moves up and down to induce in and out flow to the infusionfluid in the catheter tube 551. In some embodiments, a proper airremoval procedure and means should be used when the catheter isconnected to the drug delivery pump 552 and before insertion ( ). Inboth embodiments, the modulation mechanism can be attached to the drugdelivery pump, provided therein, in the disposable part or in a thirdunit connected to the infusion tube.

In some embodiments, the tissue treatment device can include an acousticexcitation element to stimulate the vicinity of the tissue region intowhich the drug is delivered, as illustrated in FIG. 17. In theseembodiments, the infusion catheter is combined with the acousticexcitation element 2 attached to the skin around the catheter. Thetreatment device may include a flat circular structure 5 with a centeropening for the catheter tube 3 that enters the subcutaneous tissue. Theother side of the catheter may be connected to the drug delivery pump.The acoustic excitation element can be made of piezoelectric materialssuch as PZT or PVDF. The acoustic excitation can include low or highacoustical frequencies or higher frequencies in the ultrasonic region.

The acoustic excitation device is attached to the tissue with anadhesive layer. The adhesive layer can be either on the outer ring area1 or cover also the acoustic excitation element with an acousticconducting adhesive, such as adhesive hydrogels. The acoustic excitationelement can also be covered with an acoustic conducting layer such asacoustic hydrogel or liquid. The adhesive layer may be provided coveredwith a laminate (not shown in FIG. 17) that can be peeled off by theuser before insertion of the catheter and attachment of the acousticexcitation device. Usually, for the catheter insertion, the device issupplied with a sterile needle inside the catheter (not shown in FIG.17) that is pulled out after insertion of the catheter. The acousticexcitation element can be either connected to the drug delivery pumpusing cable 4 or to a third unit or to an electronics disposed as partof the acoustic excitation treatment device, as described earlier.

In some embodiments, the tissue treatment device can use opticalradiation to stimulate the tissue region, as illustrated in FIG. 18. Inthese embodiments, the infusion catheter is combined with an opticalradiation element 301 attached to the skin around the catheter. Thetreatment device may be a flat circular structure 302 with a centralopening for the catheter tube 303 that enters the subcutaneous tissue.The other end of the catheter 303 is connected to the drug deliverypump. The optical radiation element can be made of known in the artlight sources, such as LEDs, laser diodes, lamps, etc. The opticalradiation can be in the visible or NIR or MIR regions. The light sourcemay emit pulsed light or CW light and the pulsed light source mayfurther emit pulses that are appropriate to generate photoacoustic orthermoacoustic signals on the catheter and/or in the tissue region closeto the catheter. The optical radiation device is attached to the tissuewith adhesive layer.

The adhesive layer can be provided on the outer ring area 301 or coverthe optical radiation element with an optically transparent in therelevant optical wavelengths adhesive. The adhesive layer is coveredwith a laminate (not shown in FIG. 18) that is peeled off by the userbefore insertion of the catheter and attachment of the optical radiationdevice. Usually, for catheter insertion, the device is supplied with asterile needle inside the catheter (not shown in the figure) that ispulled out after insertion of the catheter. In some embodiments, thelight source can be disposed in the drug delivery device and deliveredwith an optical fiber or several fibers to the optical radiationtreatment device. The optical radiation source can be either connectedto the drug delivery pump using a cable, connected to a third unit or toan electronics disposed as part of the optical radiation treatmentdevice, as described earlier.

In an alternate embodiment, optical radiation tissue excitation device,as illustrated in FIG. 19, coats the catheter tip with an opticalabsorption coating 801 that absorbs the wavelength or some of thewavelengths of the optical radiation. The treatment device can besimilar to the optical radiation treatment device described before. Inthis embodiment, the treatment device can be a flat circular structure800 with a central opening for catheter tube 801 to enter thesubcutaneous tissue. The other end of the catheter 802 is connected tothe drug delivery pump. The treatment device may also includes opticalirradiation elements schematically shown by 803 and 804. The opticalirradiation elements can be made of known in the art light sources, suchas LEDs, laser diodes, lamps, etc. The light source may emit pulsedlight or CW light and the pulsed light source may further emit pulsesthat are appropriate to generate photoacoustic or thermoacoustic signalson the catheter tip 801.

The optical irradiation wavelength can be either in the visible regionor in the NIR. In some embodiments, using wavelengths range of 700-1000nm provides relatively low absorption of the optical radiation in thetissue. Consequently, a larger portion of the illuminated radiation canbe scattered in the tissue and absorbed in the catheter tip. Thetip-absorbed optical radiation can induce a local hit around thecatheter tip and efficiently heats the infused tissue region, asdiscussed above in FIG. 2. Using shorter wavelengths in the visibleregion, but also in the 700-1000 nm region, can increase the portion ofthe radiation absorbed by the hemoglobin and consequently can heat moreblood or hemoglobin reach regions in the irradiated tissue region. Usinglonger wavelengths in the NIR, MIR or FIR regions can increase theportion of the radiation absorbed by the water in the tissue andconsequently can heat more of the water to reach regions in theirradiated tissue region. Also, in case of using light pulses to createphotoacoustic excitation, the portion of excitation induced at thecatheter tip, hemoglobin regions or water regions, such excitation canbe according to the absorbed radiation distribution and thephotoacoustic coefficient of each region. The produced photoacousticsignal can be measured using an acoustic sensor disposed skin attachmentstructure 800 and can be used for monitoring the energy absorbed in eachof those regions or catheter tip 801.

In some embodiments, some of the wavelengths of the above mentionedregions can be used for better control of the heated or stimulatedregion of interest. In some embodiments, at least one of the wavelengthsis absorbed by a catheter tip coating and at least one wavelength is notabsorbed by the coating to better control of the heated or stimulatedregion. The algorithm to control tissue excitation can obtaininformation from tissue temperature sensors (disclosed above), acousticsensor, optical sensor, the drug delivery profile and additional drug ortissue parameters. The algorithm can control wavelengths to regulate thedrug absorption into the blood system.

In some embodiments, a device similar to the one illustrated in FIGS. 2and 18 can irradiate the drug infused tissue region, externally orinternally, respectively, with radio frequency (RF) radiation ormicrowave (MW) radiation. Another embodiment can apply an electric fieldto the drug infused tissue region using, for instance, 2 electrodessimilar to items 301 shown in FIG. 18, to apply the field to the skin orusing electrodes disposed on the external side of the catheter tipinserted into the tissue. Also, the same device can be used to applyhigh or low frequency fields and even DC field. To improve theelectrical contact the adhesive layer can be a conducting hydrogel orother known in the art materials to attach electrodes.

In some embodiments, an additional substance can be infused into thevicinity of the drug infused region, such that the additional substancemodifies the drug pharmacokinetic and/or pharmacodynamic profile with orwithout the creation of a chemical or other reaction between the twosubstances. Specifically, the additional drug may influence either orboth of the drug infused tissue region or improving the drug'spharmacokinetics and/or pharmacodynamics profiles. This effect is notnecessarily due to a chemical reaction between the drug and theadditional substance. In some embodiments, the additional substanceimproves local blood's perfusion in the vicinity of the drug infusedregion and accordingly, reduces the absorption time constant of the druginto the blood system. This effect may be additive or synergistic to theabove described forms of stimulation. For instance, nitroprusside, whichinduces vasodilatation, can improve blood's perfusion in the druginfused tissue and improve the drug absorption into the blood system.

The additional substance can be infused into the drug infused regioneither through the same catheter or through an additional catheter,which can be attached or separated from the drug infusing catheter. Insome embodiments, the catheter can be a double-lumen catheter with 2openings inside the same tissue region or at two separate tissueregions, as shown in FIG. 20. Openings 866 and 862 of the two lumens 865and 864, respectively, can be at different depths in the tissue. In theillustrated embodiment, the double lumen catheter is secured to the skinwith a circular element 863 and an adhesive layer 860. In someembodiments, the catheter can include an additional treatment element,as discussed above, such that the combination of the additionalsubstance and the treatment provides the desired tissue stimulation ortreatment. In an embodiment of a single-lumen catheter, the additionalsubstance can be either mixed with the drug and delivered, pumped,infused, or injected together into the catheter tube. Alternatively, theadditional drug can come from a different container with a separate pumpor drug delivery device and mixed in the catheter tube according to theflow rates of the drug and the additional substance using an infusionalgorithm of the two substances. In some embodiments, the two containerscan be either disposed in the same housing, attached to each other orseparated. Similarly, in case of double lumen tube, one lumen may beconnected to the drug delivery device and the second lumen may beconnected to the additional substance delivery device. In someembodiments, a combination of the above treatment methods and/or devicescan be placed into a single device to improve its operation andefficacy.

In some embodiments, the catheter can be drawn at a 90° penetrationangle. As can be understood, other angles are possible. Smaller anglescan improve attachment of the catheter, but insertion at such angles maybe more irritating to the patient.

In some embodiments, a sensor can be added to the treatment deviceconfiguration. Alternatively, it can be added to general infusion sets,such as insulin infusion sets, and can be used to aid in detecting ifthe catheter securing element is lifted or starting to peel off theskin. The sensor can be provided in the catheter securing element sothat it is in direct contact with the skin, indirect contact through theadhesive layer or other layers attached to the skin. The sensor canmeasure pressure or skin conductivity, impedance, and/or back-reflectedoptical or acoustic signal from the skin. A change of the contact levelbetween the sensor and the skin will induce an electronic signal toeither the treatment device or drug delivery device. Then, the devicecan either inform the user to fix the attachment of the securing elementto the skin or to reinsert the catheter into the tissue in case it isdetached or to pause or stop the drug delivery or the treatment till thecatheter positioning is fixed.

In some embodiments, the treatment device can be secured to the patientusing a strap or a belt that holds the treatment device into itsposition. The strap can be placed around any part of the patient's body,depending on the location of the drug infused region and the patient'scomfort. Using such a strap can reduce the chances of the catheter to bepulled out in more demanding situations, such as jogging. For example,the strap can be placed around the abdomen, leg, thigh, arm etc. In someembodiments, the strap can have a compartment, a pocket or an adaptorfor holding the drug delivery device. In embodiments using a third unitthat supports the treatment device, the third unit can be attached tothe strap or even be embedded into the strap. The third unit can beembedded into the strap or belt, and may be connected to the catheterdisposable unit by electrical wires using a connector at the wire end.In some embodiments, the drug delivery pump can be attached to the strapand connected to the catheter disposable unit with a tube for drugdelivery. In some embodiments, the disposable unit can be attached tothe strap to further reduce chances of the catheter being pulled in moredemanding situations.

The power source can be a thin battery, such as the batteriesmanufactured by Power Paper Ltd. The electronics can be implemented on aflexible printed circuit known in the art to provide the requiredflexibility for the patient's comfort.

As can be understood by one skilled in the art, the above methods anddevices for exciting the tissue are not limited to drug-delivery pumpsand can be used with manual delivery of a drug, such as connecting asyringe (instead of a pump) to the proximal part of the catheter. Inthese embodiments, the catheter proximal part can end in a connector ora port that fits the syringe tip. Accordingly, the distal part of thecatheter is inserted into the tissue as before. In some embodiments, theproximal part of the catheter tube is short, such as it is embedded intothe treatment device, as shown in FIG. 21. In this case, treatmenthardware, which includes treatment element 602, processor 606, powersource and the abovementioned elements for tissue treatment orexcitation, are disposed in the disposable catheter unit 603, whichincludes the adhesive layer 600 for skin attachment and the catheterdistal tip 601. The syringe device can be either a regular syringe, anautomatic syringe or other automated subcutaneous drug delivery devicesthat can provide a known volume of drug and can be connected to thecatheter port for the drug delivery.

In some embodiments, the catheter unit with syringe port can be dividedinto disposable part and reusable part. In some embodiments, the syringeport comes with a plug 607 that covers the syringe port when not in use.In this case, there is no drug delivery unit in the system, thetreatment device can detect infusion of the drug and start the treatmentaccordingly. The drug infusion can be detected using the above mentionedmethods, such as flow detection, pressure detection, conductivitydetection or temperature detection. In some embodiments, a mechanicalpressure sensor 604, shown in FIG. 20, can detect the insertion of thesyringe into the port automatically, manually via a switch on thetreatment device or wirelessly by a remote control. The injectiondetection sensor can be also an optical or RF vicinity sensor thatdetects a unique RF transmission from the syringe unit or a uniqueoptical pattern or signal. The injection sensor can also get someinformation from the injection device by either RF communication oroptical reader such as barcode reader. The information can include thedrug type and dose. In some embodiments, the treatment device includes aprocessing unit 606 that can get that information and fit the treatmentalgorithm accordingly, as described before. The same treatment devicewith syringe port can be used for several injections according to eachtreatment profile and duration, battery capacity and other parameters.

In some embodiments, tissue or skin treatments or stimulation methodscan be used to treat or excite a tissue region to which a drug isinjected. In this case, as shown in FIG. 22, the excitation device 652is attached to the skin and has a circular opening for direct drugdelivery with a syringe and a needle. This option can fit injectiondevices without a needle, such as jet injectors or tissue perforationtechnologies or alternatively micro-needles injection devices. Also, theinjection syringe can have many forms for drug injection in addition tothe standard syringe, such as automatic syringes etc. An advantage ofthe device is that it is attached to the tissue prior to the druginjection. The device stimulates the injected tissue region after thedrug delivery process in order to improve the drug absorption into theblood system. The excitation profile and duration is accomplishedaccording to an algorithm that fits the drug and possibly the patient,as described earlier.

The detection of the injection can be done automatically by injectionsensor 653, manually via a switch on the treatment device, or wirelesslyby a remote control. The injection detection sensor can be an opticalsensor or an RF vicinity sensor. The injection sensor can receiveinformation from the injection device by either RF communication oroptical reader such as barcode reader. The information can include thedrug type and dose. In some embodiments, the treatment device includes acontroller or processing unit 654 that can get that information and fitthe treatment algorithm accordingly. The treatment element 651, as shownin FIG. 22, is placed around the injection area and the adhesive part650, which attaches the device to the skin around it. In someembodiments, other shapes are possible, such as many of the shapesdescribed before.

The same treatment device can be used for several injections accordingto each treatment profile and duration battery capacity and otherparameters. Before injection, the skin in the device opening can becleaned with cleaning fluid or pad such as alcohol pad through thedevice opening to prevent infections. In some embodiments, treatmentdevice can have a U-shape to facilitate skin cleaning or other shapes.

In some embodiments for drug injection, tissue or skin treatments deviceis attached to the skin after drug injection. In some embodiments saidtissue or skin treatment device is single use with a single use energysource. In some embodiments said tissue or skin treatment device isreusable use a rechargeable power source. In some embodiments saidtissue or skin treatment device is combined of disposable and reusableelements. In some embodiments said tissue or skin treatment device isactivated and starts tissue treatment automatically when applied to theskin.

The following example demonstrates a device that improves thefunctionality of existing pump-based insulin-delivery systems. Suchsystem, shown in FIG. 23, includes an insulin pump 40 and aninfusion-set 44 which delivers the pumped insulin into the tissue. Theinfusion set includes a tube 44 and a catheter 47, which is insertedinto the subcutaneous tissue. The device has two components: i) a flatheater 46, which is attached to skin around the insertion point of thecatheter, and ii) a controller unit 41, which is disposed into thecasing of the insulin pump unit. The controller unit has a switch/button48 for manual operation and two indicators 49 for “treatment is on” andfor battery status. The two components are connected by wires 43.

The controller monitors the activity of the insulin pump using anelectronic sensing element and it also controls the activity of theheating element. The controller monitors the electromagnetic emissionfrom the pump. During a bolus mode, the pump emits a well defined seriesof electromagnetic pulses at constant rate, shown as arrows 42. Forexample during a bolus dose, the paradigm 722 insulin pump from Minimedemits specific pattern of electromagnetic pulses for each 0.1 unit ofinjected insulin at a rate of 0.1 unit per second. Counting thoseelectromagnetic pulses enables one to determine the amount of injectedinsulin in the bolus initiate the operation of the heating element andadjust its parameters, such as the duration and heating temperature,accordingly. The temperature of the heater is controlled by thecontroller using a temperature sensor 45 located on the heating element.In this example the temperature of the heating element did not exceed39° C. to avoid damage to the infused insulin.

In some embodiments, the heating device can be operated manually. Inthis case, the controller controls the activity of the treatmentelement. Once a user injects a bolus of insulin using the insulin pump,the user also activates a switch/button 48 located on the controller toinitiate the heating-element operation for a predetermined duration. Thetemperature of the heater is controlled by the controller using atemperature sensor located within the treatment element (heatingelement). In this example the temperature of the heating element doesnot exceed 39° C. to avoid damage to the infused insulin.

The flat heating element used in this example has several layers. Theupper layer is a polyethylene layer which seals the element. Below thatlayer, there is an etched circuit, below which there is a copper layerfor heat distribution and mechanical support. Below that layer, there isanother sealing polyethylene layer, below which there is an adhesivetape from 3M® which is bio-compatible. The heater has a thickness ofless than 0.2 mm and his diameter is 3 cm. Thin electric wires of lengthof 60 cm with small connectors at both ends connected the heater to thecontroller unit. The power used for the heating can be 2 Watts. Theheating was turned on and off by the controller to stabilize the skintemperature at 39° C. The heat duration was set to 30 minutes, afterwhich the temperature regulation was stopped.

In general, the attachment and operation of the insulin delivery systemwith the heater is very similar to the operation of the insulin deliverysystem without the heater. The described device includes a case intowhich the insulin pump is inserted. The case contains also an electroniccircuit and batteries to operate the controller and heater. Accordingly,the patient first connects the infusion set tube to the insulin pump.Then, the patient connects the electric wires connector to the electricconnector on the heater. The patient then attaches the heater to thecenter of the catheter securing element using the adhesive tape of thecatheter securing element. The insulin catheter is then inserted to thesubcutaneous tissue either manually or using the catheter springinserter. The mechanism of the catheter insertion is the same as usualusing the same insertion module and following the same steps. The heatercan be attached to the catheter securing element before insertion. Thepatient can connect the infusion set tube to the catheter. The patientconnects the wires coming from the heater to a designated connector onthe controller. The operation of the bolus is either automatic or manualas described before.

Another heater structure is shown in FIG. 24. In this case, the heater34 is U shaped and attached to the skin around the insulin infusion set30. The advantages of this configuration are that the heater can be anindependent unit that fits many of the commercial infusion sets and alsothe thermal insulation between the insulin and the heater is kept. The Ushaped heater can be thin or thicker and be built in many ways known inthe art. The U shaped heater shown in FIG. 24 is made of heat conductingmetal and has a resistor 31 for heating and a temperature sensor 32 forcontrolling the temperature.

Another heater structure is shown in FIG. 25. In this case, the heater37 is circular and attached to the insulin infusion set around thecatheter prior to insertion into the body, as described above. The shapeof the cuts 39 enable attachment of the heater to the infusion set priorto removing the catheter cover, although the catheter cover diameter maybe larger then the central opening. It is important to remove thecatheter cover or cup as the last operation before insertion of thecatheter to the tissue because of safety and sterility issues. However,having the cuts 39 of the heater enable using a heater with an optimizedcentral opening diameter without the limitations of the catheter cover.This is important in order to optimally heat the drug infused tissuevicinity on one hand and keep the thermal insulation between the insulinin the catheter and the heater on the other hand. The heater can be anindependent unit that fits many of the commercial infusion sets. Theheater includes also a temperature sensor for controlling thetemperature. The thickness of this heater may be about 0.2 mm.

To demonstrate the improvement of the insulin pharmacodynamics of thedevice described in this example, a euglycemic glucose clamp study wasperformed, using the following protocol. An insulin dependent diabeticvolunteer treated with an insulin pump arrived after an overnight fastprior to taking a morning bolus with the pump. The subject lied down insupine position. The subject's blood glucose level was stabilized at 100mg/dl. A bolus of insulin was given using the subject's insulin pump(0.15 U/kg). The pump was halted from the end of the bolusadministration. A 20% dextrose drip was adjusted to keep the bloodglucose level at about 100 mg/dl. Frequent blood sampling (every 5-10min) was used for adjusting Glucose Infusion Rate (GIR) as required fortight control of the euglycemic glucose level.

The above described procedure was performed in the same subjects underthe same conditions with and without using the heating device. A typicalresult is shown in FIG. 26 a. The two graphs show the GIR in glucosemilligrams per minutes per subject's kg vs. time. The solid line showsthe GIR without the heating treatment, while the dashed line shows theGIR on the same subject with heating. It can seen that the time to peakaction was significantly shorten from 75 min without heating 21 to 50min with heating 20. Also the GIR decrease, which is an indication forinsulin clearance out of the circulation and cessation of it's systemiceffects was much faster with heating 22 then without heating 23. Both ofthose parameters are important for better control of the glucose levelsince the delay of the peak action may cause glucose rise immediatelyfollowing meals and the residual insulin level in the tissue and in theblood may induces late hypoglycemia and promote an error in theestimation of the effect of the next insulin bolus. Those two parameters(the delay to insulin peak action and the residual insulin level), whichare important for tight glucose level regulation are very important alsowhen automatically controlling the subcutaneous insulin infusion rateusing a continuous glucose sensor and a control algorithm. There aremany attempts to compose such an “artificial pancreas” since thedevelopment of continuous glucose monitors. In this case, any delay suchas the current delays of the insulin absorption and action time, anyvariability in this delay and any variability in the residual insulinlevel in the body induces an error for the control algorithm that willresult in less tight glucose regulation. Thus, another use of themethods and devices by the present invention is to combine them with aglucose sensor, insulin delivery device and a control algorithm toprovide a better accuracy and robustness of a closed loop glucose levelcontrol system.

The same protocol and meal tolerance test protocol, in which diabeticpatients had liquid meal and used the same dose of insulin bolus (0.15U/kg) using their insulin pump, again with and without heating theinfused region using the same device. The insulin blood concentrationwas measured on blood samples using insulin immunoassay kit of DRG. Thepharmacokinetics results or the profile insulin concentration in theblood after bolus infusion from both experiments is shown in FIG. 26 b.The graphs are the average of 11 subjects that had bolus of insulin 0.15U/kg with and without the heating device. The graph shows clearly thatthe blood insulin concentration for the same amount of infused insulinis significantly higher at the initial 2 hours when using said heatingdevice. The 1 hour area under the curve improvement or the amount ofabsorbed insulin in the blood is more then 30%. This improvement in theinsulin pharmacokinetics leads to improvement in the insulinpharmacodynamics, such as shown in FIG. 26 a, reducing the time to onsetof action, reducing the time to peak action and the other effectsdescribed before.

Medical and/or Cosmetic Devices for Drug Delivery

Some embodiments of the present invention relate to a method and devicefor improving the performance of implantable devices or of devicesplaced on the skin. Combination of radiation sources and/or heat and ormechanical vibrations and or suction is applied to the tissueautomatically by attaching the device of the present invention next toan implantable device, a percutaneous catheter, or a device placed onthe skin serving either as a sensor, a catheter or a module that secretto the tissue (the first device). The device of the present inventioncan also be part of the catheter which has one section inside the tissueand another section that connects to a unit outside the tissue. Theindividual excitation source properties, or the combination ofexcitation sources as well as the properties of each excitation source(such as amplitude, phase, frequency) as well as the relative ratio andtiming between the various excitation sources may be automaticallycontrolled by a processor in order to achieve a desired response fromthe tissue next to the device. Activation of the first deviceautomatically triggers the operation of the device of the presentinvention or the device of the present invention detects operation ofthe first device and starts to operate by applying excitation to thetissue, or the device of the present invention operated at predeterminedtimes for a predetermined length of time. The tissue response to theexcitation enhances the functionality of the first device. Thisenhancement may be induced but not limited by altering the kinetics ofmolecules transport between the first device and the tissue. Or thetissue response to the excitation enhances the kinetics of moleculestransport between the catheter tip placed inside the tissue and thetissue around it.

The excitation or excitation-detection device will be referred to as thesecond device. The first device and the second device may be placedeither inside the tissue, or on the skin or the second device may beplaced outside the tissue while the first device is inside the tissue.The first device may be mechanically or electronically, or mechanicallyand electronically connected to the second device or the second devicemay be placed on the surface of the tissue above the first device or thesecond device may be a section of the first device.

The second device includes at least one of the following excitationsources or at least one combination of two from the following excitationsources: at least one heat source (like a heat resistor) or at least onesuction port activated by a pump or at least one mechanical vibrationsource or at least one ultrasound transmitter or at least one ultrasoundtransducer, or at least one electrical electrode or at least one lightor laser light emitting source, or at least one optical fiber, or atleast one electromagnet or permanent magnet or a combination of morethen two of heat, vibrations, suction, ultrasound, light, electronicelectrode, magnet. The light source may emit pulsed light or CW lightand the pulsed light source may further emit pulses that are appropriateto generate photoacoustic or thermoacoustic signals on the first deviceand/or in the tissue surrounding the first device.

The combination of excitations generated by the second device reactswith the region of tissue surrounding the first device and the reactionenhances the functionality of the first device. Or the tissue responseto the excitation or combination of excitations enhances the kinetics ofmolecules transport between a catheter tip placed inside the tissue andthe region of tissue around it.

The second device includes at least two parts wherein one part is usedto fix the second part on its position relative to the tissue. One partmay further be disposable while the other part that contains theelectronics is reusable. However, it is clear to those skilled in theart that the device may be made in one part or in more than one part andthat the electronics, the controller, the power supply and fieldgenerating modules may all be housed in one case or in more than onecase. The power supply may also be a battery or the device may beconnected to a power line.

Some embodiments relate to a percutaneous catheter that is used togetherwith insulin pump to deliver insulin subcutaneously this part isreferred to as the “the first device”. The second device is placed onthe tissue surface above the catheter and the stimulation from seconddevice reduces bio-foiling of the catheter. The second device mayfunction independently from the first device or it may communicate (inwire and/or wireless modes) to the first device. The second device mayalso use the power source of the first device.

In some embodiments, the percutaneos catheter—“the first device” emitslow RF field generated between the wire and an external electrode orbetween electrodes on the wire “the second device”. This field altersthe tissue response to the foreign body and allows better functionalityof the catheter.

In some embodiments, an indwelling or implantable device—“the firstdevice” is made in structure and material composition to enhance themechanical vibrations caused by the second device. Such enhancement canbe achieved by making the body of the first device to resonate with theradiation field generated by the second device which can be ofultrasound waves. The material of the first device can be made to absorblight radiation and emit ultrasound wave by the photoacoustic orthermoacoustic effect. An electrode formed along the first device caninteract with an applied electromagnetic field or magnetic fieldgenerated by the second device.

In some embodiments, the percutaneous catheter is a catheter that isused together with insulin pump to deliver insulin subcutaneously—“thefirst device”. The second device, placed on the surface of the tissueexcites the tissue with light or heat or mechanical vibrations orsuction or Electrical current or Ultrasound or RF frequencies or acombination of at least two from heat, vibrations, suction, ultrasound,light, electronic electrode, magnet, RF frequencies that causes areaction to occur in tissue next to the catheter. This reactionstimulates the tissue reduces bio-foiling and improves the dynamics ofinsulin transfer tissue.

In some embodiments, the percutaneous catheter is a catheter that isused together with insulin pump to deliver insulin subcutaneously—“thefirst device”. The second device, placed on the surface of the tissueirradiates the tissue with light that causes photoacoustic orthermoacoustic reaction to occur on the percutaneous catheter. Thisreaction stimulates the tissue reduces bio-foiling and improves thedynamics of insulin transfer to the tissue.

In some embodiments, the first device is an adhesive pad containingadhesive to the skin and matching layer. The matching layer may beliquefied gel or solidified gel. The composition of the said gel mayinclude molecules other then water. The second device includes a powersource and exciting source. The power source may be a battery. Thebattery may be replaceable or embedded in the device. The excitingsource may be detachable from the device or embedded in it. The batteryprovides power to the exciting source. The exciting source is acombination of light or laser light illumination and ultrasonic source.The excitation from the second device is used to enhance the transportkinetics of molecules present in the gel to the tissue. The first andsecond devices may be mechanically configured in two cases or in onecase.

FIG. 48 illustrates an exemplary drug delivery device, wherein the firstdevice or the first part is an indwelling catheter of an infusion pumpinserted to the tissue, according to some embodiments of the presentinvention. The second device or the second part combines ultrasoundtransducer with light or laser light source in one case. The casefurther includes electronic driving circuits, controller and powersource. The case is positioned over the skin above the catheter of thefirst device by an adhesive tape with mechanical attachments to hold thecase on the tape.

FIG. 49 illustrates an exemplary drug delivery device, wherein anattachment to the skin includes a power source, exciting source,adhesive to the skin and matching layer between the exciting source andthe skin, according to some embodiments of the present invention. Thematching layer may be liquefied gel or solidified gel. The compositionof the said gel may include molecules other then water. The power sourcemay be a battery. The battery may be replaceable or embedded in theattachment. The exciting source may be detachable from the attachment orembedded in it. The battery provides power to the exciting source. Thebattery can be made by ink deposition on a polymer material—Power PaperLtd., Petch Tikva, Israel www.powerpaper.com. The exciting source is acombination of light or laser light illumination and ultrasonic wavessource. The exciting source ultrasonic part can be made from a thinlayer piezoelectric material put on a layer of light emitting polymersuch as poly phenyl vinylene (PPV). The thin piezoelectric materiallayer can also be made of Polyvinylidene Fluoride (PVDF). If the layerof piezoelectric polymer can be made to pass the light emitted by thelayer of light emitting polymer then the layer of light emitting polymercan be on top of the piezoelectric material layer.

Method and System for Drug Delivery with Tissue Irradiation

Some embodiments of the present invention relate to apparatuses, methodsand devices to improve and stabilize the pharmacokinetics andpharmacodynamics of a drug infused into the tissue by a catheter andabsorbed into the blood system. The apparatus and devices describedherein apply additional treatment or stimulation to the region of tissuewhere the drug is infused. The additional treatment includeselectromagnetic radiation, which as described herein more includes lightirradiation of the tissue.

According to some embodiments, there is provided a device for improvingthe performance of catheter based drug delivery devices, whether thecatheter is an external element to the pump or an element embedded intoa pump mechanism, which also combines electromagnetic radiationtreatment, for example, from a source of electromagnetic radiation.Application of the electromagnetic radiation treatment may be performed,in some embodiments, substantially at the same time as the drug infusionoperations are performed. The device described herein can also be partof the catheter which has one section inside the tissue and anothersection that connects to a unit outside the tissue.

The electromagnetic radiation treatment is applied to a tissue region towhich the drug is delivered to expose it to electromagnetic radiationand/or to an effect caused by electromagnetic radiation to improve thedrug pharmacokinetics or pharmacodynamics. The effect may include, butis not limited to, heating, acoustical stimulation, light basedstimulation and the like.

The present disclosure radiation treatment of a region of a tissue byany type of electromagnetic radiation in conjunction with the infusionof the drug into a body of a patient, including optical radiation, tocause different type of treatment effects (or stimulation).

For example, the described herein is the use of optical radiation totreat the skin so as to achieve improvement of pharmacokinetics and/orsome other pharmaceutically related parameter for the administration ofa drug through a pump system, for example through infusion. Treatment oftissues with optical radiation according to the present disclosure maybe performed with light at a variety of wavelengths from infrared to lowultraviolet or shorter than ultraviolet wavelengths. Furthermore, avariety of instruments may be used for providing such light, including,but not limited to, lasers, such as laser diodes, including singleelements or laser diode bars or arrays, VECSELs, or solid state lasers,fiber lasers, other types of lasers, LEDs, mercury arc lamps, xenon arclamps, other types of lamps and the like. The light source may emitpulsed light or continuous wave light, or a combination thereof. Ifpulsed light is emitted, then, in some embodiments, one or morecharacteristics of the pulses are determined according to one or morepharmaceutical requirements of the drug being administered.

The instruments may emit a broad spectrum light and/or a narrow spectrumlight. If the instruments emit a broader spectrum light than isrequired, one or more filters may be employed to reduce the spectrum oflight treating the tissue. Radiation devices used to irradiate thetissue may also include mirrors, lenses, fiber optics and other likecomponents to focus the light in a specific region or regions.

In circumstances where the radiation unit generates light to be appliedto the tissue, the light may include wavelengths in the range of fromabout 300 to about 3,000 nm. The light may be a broad spectrum light,including a majority of such wavelengths. In some embodiments, generatedlight includes radiation in the near infrared wavelengths and/or shorterwavelengths of light and/or longer wavelengths of light. For example,for near infrared light, the wavelengths include the wavelength rangefrom about 700 to about 1000 nm. For light having longer wavelengths,the wavelengths are at the infrared region. Higher frequencyelectromagnetic radiation, such as electromagnetic waves in the TeraHertz range (corresponding to waves in the millimeter range, microwavesor RF (radio frequency) are also possible.

In some embodiments, low frequency RF energy is applied at a level(e.g., power level) which is non-ablative. For example, radiofrequencyenergy in the range of 50 to 2,000 kHz may be selected so as to benon-ablative for the subject. RF energy may be applied as a plurality ofpulses. In some embodiments, a single or multiple electrodes may beused. The electrodes may contact the skin and may, in someimplementations penetrate the skin. In some embodiments, a catheter isused for drug delivery with at least one electrode being incorporated inthe catheter. Each electrode may be constructed from one or moreconductive metals, including, but not limited to, platinum, iridium,gold, silver, stainless steel, Nitinol, or an alloy of these metals.

In some embodiments, the device includes a catheter inserted into thetissue to infuse a substance into that tissue region. The tissue regioncan be one of the skin layers or the subcutaneous tissue or deepertissue elements within any organ or viscera.

The catheter may have also a securing mechanical part or device thatadheres to the skin and secures the catheter into its location toprevent it from being pulled out accidentally. The proximal end of thecatheter may be connected to a drug delivery device which controls theinfusion profile of the drug. The drug delivery device controls also theadditional treatment (e.g., irradiation) applied to the infused tissuearea. The drug delivery device and the treatment module (e.g., theradiation unit) may be in communication with other to communicate databased upon which operations of the drug delivery device and theradiation unit may be performed. The communication may be either wiredor wireless. Parts of the treatment device may be disposed inside thedrug delivery device or outside of it. The drug delivery device mayinclude a drug delivery pump, such as an insulin pump.

The pump may include an electronic processing unit to determine,according, for example, to a predetermined protocol, implementedprocedure, any additional inputs and drug infusion profile when and towhat extent electromagnetic radiation should be applied. The pumpelectronic processing unit may, in some embodiments, communicate with aprocessing unit of the treatment module. The processing unit of thetreatment module determines according to a predetermined protocol, aprocedure, and according to drug infusion profile when and to whichextent the electromagnetic radiation should be applied. The pumpelectronic processing unit and/or the treatment device processing unitregularly query the status of the pump by, for example, using built-incommunication capability of the pump. The received data is then used todetermine the electromagnetic radiation treatment parameter(s).

Sensors in communication with the source of electromagnetic radiationmay detect the drug being delivered into the patient's body through thecatheter. In response to the detected drug delivery, the treatmentmodule applies a treatment (e.g., radiation) according to apredetermined protocol or procedure. In some embodiments, the treatmentmodule includes a sensor that can detect the drug infusion flow insidethe catheter and deliver the information to the device processing unit,which then determines the electromagnetic radiation treatmentparameter(s). The drug flow may be detected, for example, opticalsensors that detect the drug flow through the catheter (e.g., incircumstances in which a transparent or translucent catheter is used), alaser Doppler sensor, an ultrasonic Doppler sensor, a pressure sensor, aconductivity sensor and/or an inductance sensor that can measure changesin the flow rate of the infusion fluid, under induced magnetic field(for example). The drug flow sensor may detect not only the existence ofa drug infusion flow, but also the infusion rate, and uses theinformation to determine, at least in part, the treatment procedure. Thedrug infusion sensor may detect the electromagnetic or acoustic emissionof the drug delivery pump motor or electronics. In some embodiments, thedevices detect additional parameters pertaining to the tissue and usethat information as well to determine or control the treatment procedure(e.g., compute parameters germane to the treatment procedure).

Referring to FIG. 18, the light source can be disposed in a third unit(not shown) and the generated light can be delivered with an opticalfiber, or several fibers, to the optical radiation element 301. Thethird unit can be attached externally to the drug delivery device toimprove the user's comfort. Under these circumstances, the fiber orfibers can be disposed proximate to the catheter tube 303, for example,the optical fiber(s) can be attached to the outer shell defining thecatheter tube 303 and extend along the tube. The optical fiber(s) andthe tube 303 could then be separated at around the drug delivery devicesuch that the drug catheter tube 303 would be extended and be coupled tothe drug delivery device (not shown), and the fiber or fibers would beconnected to a third unit that includes at least one light source. Thethird unit may also include a power source and a controller (not shown).When drug delivery starts, e.g., during a drug bolus delivery, theoccurrence of the drug delivery operation can be communicated to thethird unit, either actively by direct communication between the drugdelivery device and the third unit, or passively through a signalsgenerated by a sensor detecting the occurrence and/or commencement ofthe drug delivery operation e.g., electromagnetic emission by the drugdelivery device.

The optical radiation element 301 can be disposed in a catheter securingunit such as shell (not shown) encasing the catheter tube 303. Oneeffect caused by the electromagnetic radiation is heating of theradiated tissue region. The application of electromagnetic radiation maybe used to control the temperature of the tissue region into which thedrug is delivered. Temperature control can be used for setting a profileof temperature rise at a known rate, followed by temperaturestabilization for a pre-determined time period and concluding byreturning to the tissue to its regular temperature. This profile can beapplied by, for example, illuminating the drug infused tissue regionwith electromagnetic radiation. The temperature profile can be appliedto a larger region than the drug infused tissue region to circumventlight scattering in the tissue. Doing so may improve blood perfusion inthe vicinity of the drug infused tissue area, thus further increasingdrug absorption rate into the blood system through increase of theavailable absorption volume. The temperature profile can be applied to aregion smaller than the drug infused tissue region, thus enablingconservation of energy (e.g., in circumstances in which a battery with alimited energy capacity is used).

Another exemplary device to perform irradiation of radiation at the areaof a tissue into which the drug is delivered is schematically shown inFIG. 27. As shown, a treatment device 2710 includes an infusion catheter2703 and at least one radiation source element 2702 attached to the skin(not shown) in an area around the catheter 2703. The treatment device2710 further includes a circular structure 2705 with a hole 2711 in itscenter for the catheter tube 2703 that is subcutaneously inserted intothe skin tissue. The other side of the catheter 2703 is connected to thedrug delivery pump (not shown). Radiation source element 2702 mayinclude one or more light sources 2712.

As further shown, a temperature sensor 2706 is disposed in contact withilluminated skin region to regulate the skin temperature to the requiredtemperature according to a temperature control procedure or temperatureprofile. Regulation of the tissue temperature may be based on measuredtemperature values detected at a sensor 2706. The temperature sensor 6is connected to a controller unit 2713 disposed in the catheter 2703 orin the drug delivery device (not shown) and/or in an third unit (notshown). In some embodiments, the temperature is between 32-40° C. Thistemperature range has been found to have sufficient effect on the tissuewhile not causing damage or injury to the tissue. Temperaturestabilization profiles/procedures may be executed using controllersand/or ASICs. A skin cooling system may be used, as described, forexample in U.S. Pat. No. 5,344,418, the content of which is herebyincorporated by reference in its entirety. The skin or tissue damagedepends on the applied temperature and the heat exposure time. For anexposure period that is relatively short e.g., a few minutes, evenhigher temperatures, for example, temperatures of up to of 42° C. may beused. Under some circumstances, lower temperatures may be required. Forexample, Novolog Insulin requires maximal temperature of 37° C. in theinsulin infused tissue region. However, under those circumstances, theskin temperature can be slightly higher than that, as the insulininfused tissue region could have a lower controlled temperature.

An additionally and/or alternatively, a temperature sensor (not shown)is located inside the catheter tube 2703. This temperature sensorenables more direct control of the temperature of the drug infusedtissue region, in turn enabling potentially better stabilization of thedrug chemical processes or pharmacokinetics or absorption into the bloodsystem or pharmacodynamics that can be achieved. In situations in whichthe drug delivered is insulin, it is important to reduce the variabilityof the temporal profile of the insulin absorption into the blood and tomore closely regulate temperature control.

The at least one radiation source element 2702 and one or two oftemperature sensors may be connected to the drug delivery pump through acable 2704. Under these circumstances, the drug delivery pump includesthe power source and the controller of the treatment process (notshown).

A circular structure 2705 that covers at least one radiation sourceelement 2702 may be thermally isolating such that the flat circularstructure 2705 reduces the heat dissipation to the environment in Use ofthe circular covering structure 2705 also facilitates the thermalregulation (e.g., stabilization) of the infused tissue area insituations in which the environments and/or ambient temperature undergochanges.

The at least one radiation source element 2702 generates radiation totreat the drug infused tissue area as described herein. In someembodiments, the tissue from any heat produced in the course ofgenerating the actual radiation applied to the tissue. For example, ifthe radiation includes light, then the transformation of electricalenergy into light energy, whether by radiation source resistance ornon-radiative transitions. Under these circumstances, the combination ofgenerated heating and radiation is applied to the tissue to betterand/or more efficiently produce the desired effect.

In some embodiments, the device 2710 as shown in FIG. 27 is attached tothe skin with an adhesive tape 2715. The adhesive layer 2701 of the tape2715 can also cover the at least one radiation source element 2702, forexample, with a transparent adhesive. The adhesive tape 2715 isinitially covered with a laminate (not shown) that is peeled off by theuser before insertion of the catheter 2703 and the radiation sourceelement 2702. Generally, to facilitate catheter insertion the device issupplied with a sterile needle disposed inside the catheter 2703 (notshown) that is removed after insertion of the catheter 2703 into therequired tissue area. The adhesive layer of tape 2715 may partiallyabsorb the electromagnetic radiation to increase the outer layer of theskin heating, which may be required for certain heating depthdistribution for optimization of heating profile and/or the heatingefficiency.

Referring to FIG. 28, another exemplary treatment device is shown. Thetreatment device includes a catheter tube 2803 configured to directelectromagnetic radiation through the tube and to illuminate radiationemitted at the tube end 2801 at the drug infused tissue region (notshown) As shown, the light from the at least one radiation source 2806is coupled into tube 2803 near the drug delivery device 2804 through alight coupler 2807. The radiation source may be part of the drugdelivery device 2804. Alternatively, a radiation source 2806 can behoused in a separate third unit as shown, that is attached to the drugdelivery device 2804. To facilitate light coupling into the tube 2803,the radiation source 2806 may be attached to the tube 2803 at the lightcoupler 2805, and be otherwise disposed so as to be substantiallyaligned with the longitudinal axis of the tube, while the drug flowingfrom drug delivery device 2804 is enters the tube 2803 from the side.Generated light is thus directed through the length of tube 2803 untilit decoupled at the tube end 2801 located proximate to the drug infusedregion. The decoupled radiation is subsequently absorbed by the tissueregion. The generated light is directed through any bend in the tube2803

The catheter tip 2801 may be secured to the skin using catheter securingdevice 2802 with an adhesive layer 2800. In some embodiments, thesecuring device 2802 also includes at least one temperature sensor onthe skin, the catheter, or at the drug infused tissue region tofacilitate temperature regulation of the tissue. The temperature of thedrug infused tissue region may be monitored non-invasively through thecatheter, for example, by measuring the tissue IR emittance or byimplementing other procedures for optical non-invasive temperaturemonitoring.

Referring to FIG. 29, an exemplary device to couple and direct lightthrough a tube that also carries a drug is shown. In some embodiments,the light is guided inside the drug delivery tube 2919 by the tube walls2916. The material of tube walls 2916 is selected based on the type oflight being guided and to provide acceptable light compensationperformance for any light scattering that occurs. The drug is deliveredby a drug delivery device 2910 through a tube connector 2911. At leastone light source is shown schematically by box 2912. Generated lightrays 2914, shown schematically by the bouncing line pattern is directedand/or controlled using optical device (e.g., lenses, couplers, etc.) orthe waveguide 2913 to provide appropriate coupling efficiency into drugtube 2919. The difference between the refraction index of the drug 2918and the tube wall 2916 enable the light rays 2914 to propagate throughthe tube To achieve efficient guidance of the light, the core materialin the waveguide (which in these circumstance will include the drugmaterial 2918) is required to have a higher index of refraction than thewalls 2916 (the walls of the waveguide are referred to as the“cladding”). For example, in some embodiments, a drug is administeredwhich, when diluted in water, has an optical index of refraction ofapproximately 1.33. If, under these circumstances, the tube wall 2916 ismade from a polymer having an index of refraction of approximately1.4-1.5, then light guidance will not be efficient (because thewaveguide's wall have an index of refraction higher than that of themedium constituting the core). However, the efficiency of light guidancecan be significantly improved by choosing polymers having a lower indexof refraction for the tube wall 2916 and/or coating the inner side ofthe tube 2915 (i.e., the surfaces of the tube wall 2916) with a thinlayer of light reflecting coating 2920 that includes, for example, oneor more metals such as aluminum, silver, gold, etc. The reflectingcoating can be coated by a protection layer made of polymer or otherbiocompatible materials. Under these circumstances, the light will beguided through the resultant coated tube with very small loss. Theexternal surfaces 2917 of the tube walls 2916 may also be coated with areflective coating.

The light wavelength is selected to have a very low absorption rate bywater. Suitable light waves are those having wavelengths in the range of300-1300 nm. The inner coating 2920 can be also of a polymer having alow index of refraction, to achieve better guidance of the light.

Referring to FIG. 30, showing another exemplary treatment device inwhich the drug delivery tube also functions as a waveguide, the outerside of the drug delivery tube 3029 can be coated with a reflectingcoating 3027. A drug delivery device 3020, a tube connector 3021 and alight source 3022 may be similar to the respective components/modulesshown in FIG. 29. The optical shaping coupling element 3023 isconfigured to optimize the coupling efficiency for light (shownschematically as the bouncing ray lines) 3024. Under thesecircumstances, the light 3024 is guided through the drug solution 3028(constituting the waveguide's medium core) and the transparent wall ofthe tube 3026. The reflecting coating may also be covered by aprotection layer. Such a waveguide implementation can also be usedwithout coating the outer surfaces of the tube 3026 with the reflectingcoating 3027 because the index of refraction of air (1) is smaller thanthe index of refraction of the polymer tube 3026. However, any objecttouching the tube, for example, the abdomen of the patient could inducelight leakage. In some embodiments, the tube wall 3026 is made of twolayers with different indices of refraction such that the outer layerhas smaller index of refraction and serves as cladding for the opticalwaveguide Similar to the arrangement shown in FIG. 29, the walls 3026may also be coated with a reflective coating 3025.

Referring to FIG. 31, another waveguide implementation is shown. In thearrangement of FIG. 31, the light 3136 is shown schematically bybouncing line rays in the tube wall. A drug delivery device 3130, a drugdelivery tube 3139, a tube connector 3131 and a radiation source 3132may be similar to the respective components/modules described inrelation to FIGS. 29 and 30. The optical shaping coupling element 3134is mounted in mechanical adapter 3133. Reasonable (possibly optimal)light coupling efficiency can be achieved by structuring the waveguidesection as a circular ring having a shape similar to the shape of thetube 3139 in cross-section. To couple the light into the circular ringwaveguide, suitable optical elements, such as lenses, asphericalcomponents, diffractive optical elements, fiber illuminators and/ormounted light sources having a circular shape may be used. For example,an optical shaping coupling element 3134, e.g., a lens, can be used tocause light generated at the light source 3132 to be coupled into thecircular ring-shaped waveguide. The arrangement shown in FIG. 31 mayalso be used without the inner coating 3135 and/or outer coating 3137 ofthe tube because the index of refraction of air (1) is smaller than theindex of refraction of the polymer tube wall 3136. In some embodiments,the index of refraction of the drug solution 3138 is also smaller thanthe tube wall's index of refraction. However, under those circumstances,any object touching the tube, such as, for example, the abdomen of thepatient, will induce light leakage.

In some embodiments, the reflecting coating is covered also by aprotection layer. The tube wall 3136 may be made of two layers havingdifferent indices of refraction such that the outer layer and the drugsolution have smaller indices of refraction and serve as the cladding,while the inner layer of the wall functions as the waveguide core toguide the light. The tube wall 3136 may be made of three layers withdifferent indices of refraction such that the outer layer and the innerlayer have smaller indices of refraction and thus serve as the cladding,while the middle layer of the wall serves as the core to guide thelight.

Referring to FIG. 32, an exemplary treatment device 3266 in which anelectromagnetic radiation element is located within the cathetersecuring device and radiates the tissue through the catheter is shown.In this arrangement, an infusion catheter 3265 is combined with at leastone optical radiation element 3264 that couples the light into aproximal part 3261 of the infusion catheter 3265. A catheter securingdevice 3266 includes a circular structure 3263 with a hole 3267 in itscenter through which the catheter tube 3261 enters the subcutaneoustissue. The circular structure 3263 is attached to the tissue with anadhesive layer 3260. The adhesive layer 3260 may be initially providedwith a laminate (not shown) that is peeled off by the user beforeinsertion of the catheter and the connection of the optical radiationelement 3264. Electromagnetic radiation source(s) can illuminate thedrug infused tissue region through the skin. In this arrangement theadhesive layer 3260 can be either around the illuminated skin area orcover the illuminated skin area with an adhesive that is opticallytransparent in the relevant optical wavelength(s). The other side of thecatheter 3265 is connected to a drug delivery device (not shown).

Generally, for catheter insertion, the device may be supplied with asterile needle (not shown) disposed inside the catheter that is removedafter insertion of the catheter. The power source for the opticalradiation element 3264 can be disposed in the catheter unit 3266.Alternatively, the power source for the optical radiation element 3264may be disposed in the drug delivery device and connected with a wire tothe optical radiation element 3264. Alternatively, in some embodiments,the power source for optical radiation element 3264 can be disposed in athird unit (not shown) connected with wires to the optical radiationelement 3264. In some embodiments, the third unit can be attachedexternally to the drug delivery device to improve the user comfort.

Referring to FIG. 33, another exemplary treatment device that includes awaveguide to irradiate radiation at the drug infused tissue area througha catheter end is shown. In the illustrated example of FIG. 33, theelectromagnetic radiation is light. However, other types ofelectromagnetic radiation may be used to irradiate the drug infusedtissue area. As shown, light from the at least one light source 3305 iscoupled into a catheter 3310. The light source 3305 can be part of thecatheter securing device 3304, as shown, or alternatively may bedetachable (similar to the arrangement shown, for example, in FIG. 6).To facilitate light coupling into the catheter 3310, the light source3305 can be aligned on the same longitudinal axis of the catheter tube3310, while the drug enters catheter tube 3310 at the side of the tube.

In some embodiments, the drug is imparted from the drug delivery devicethrough a tube 3301. The tube 3301 may include a connector 3315 havingone section 3302 attached to the tube and a second matched section 3303attached to the catheter 3310. The light, schematically depicted by thebouncing ray lines is guided through the catheter 3310 until it exits atthe catheter end contacting the tissue enters the drug infused areawhere it is absorbed by the surrounding tissue of the area.

As further shown in FIG. 33, the light is guided inside the cathetertube 3310 by the tube walls 3308. The light is shaped and controlled(e.g., controlling the light's direction) using coupling opticalcomponent 3306 which may include a lens or some other type of opticaldevice, or by a waveguide, to provide suitable coupling efficiency ofthe light into the catheter tube 3310. The light controlled by thecoupling optical component 3306 passes through a transparent wall 3320inside the drug delivery tube 3301. As previously explained, the lightgenerally propagates within the tube 3301 because the difference betweenthe refraction indices of the drug (functioning as the core medium) andthe tube wall 3308. Thus, the light guidance characteristics of thewaveguide can be improved by choosing a lower index of refractionpolymers for the catheter tube 3310 or coating the inner side 3307 ofthe catheter tube 3310 with a thin layer of light reflecting coating,including coating that include one or more of aluminum, silver or gold.The reflecting coating can be coated by a protection layer of polymer orother biocompatible materials. Under these circumstances, the light willbe guided by the coated tube and sustain only small losses. The outerside 3309 of the catheter tube 3310 is generally not coated.

In some embodiments, the light wavelength (or range) is selected so thatsmall absorption of light by water results. For example, a suitablelight wavelength range includes wavelengths in the range of 300-1300 nm.Use of light having a wavelength(s) in that range reduces lightabsorption by a solution containing the drug (which generally has a highconcentration of water) thus preventing heating of the solution. Thesewavelengths may be used in situations in which the drug should not beheated above a maximum temperature, such as for drugs that includeproteins for example.

A catheter tip 3311 may be secured to the skin using the cathetersecuring device 3304 with an adhesive layer 3300 in a manner similar tothat described in relation to other figures of the present disclosure.At least one temperature sensor (not shown) may be placed on one or moreof the skin, the catheter, or the drug infused tissue region. The atleast one temperature sensor is configured to regulate (e.g., stabilize)the tissue temperature. In some embodiments, the temperature of the druginfused tissue region is monitored non-invasively through the catheter3310, for example, by measuring the tissue IR emittance or other byusing other optical non invasive temperature monitoring techniques.

Referring to FIG. 34, in some embodiments, an outer side 3428 of thecatheter tube can be coated with a reflecting coating 3429. A tube 3421,which delivers the drug from the drug delivery device (not shown) iscoupled to a connector 3415 having sections 3422 and 3423. The devicefurther includes a radiation source 3425 similar to the radiation sourcedepicted in FIG. 33. An optical shaping coupling element 3426 used toefficiently couple light into the catheter tube. As shown in thearrangement of FIG. 34, light, depicted schematically by the bouncingray lines 3430, is guided in both the drug solution and the transparentwalls of the catheter tube 3428. The reflecting coating 3429 may befurther covered by a protection layer. In the depicted arrangement, acoating may not be provided for inner walls 3427 of the catheter tube3428.

The waveguide implementation of FIG. 34 can also be used without coatingthe outer side of the tube 3428 with a reflecting coating because theindex of refraction of the air (1) is lower than the index of refractionof the tube 3428 (typically polymer based). However, when the lightenters the catheter portion which is inside the tissue, the light willleak out of the waveguide because the tissue index of refraction ishigher (see FIG. 36). The catheter portion at which the light shouldscatter out of the catheter tube may be coated with partially reflectingcoating as will be described in greater detail below. In someembodiments, the tube wall 3428 is made of two layers with differentindices of refraction such that the outer layer has smaller index ofrefraction and thus serves as cladding for the optical waveguide (notshown). In some embodiments, a catheter securing device 3424 withadhesive layer 3420 may be provided.

Referring to FIG. 35, another guidance device to implement a furtherguidance scheme is depicted. As shown, the light, representedschematically by the bouncing ray lines, is guided in a tube wall 3548of a catheter 3551. A tube 3541 from the drug delivery device includesan connector 3515 with having, for example, sections 3542 and 3543(similar to the configuration of the corresponding connector depicted inFIG. 33). The treatment device also include a radiation source 3545(similar to that of FIG. 33). Also included is a catheter securingdevice 3544 with an adhesive layer 3540. An optical coupling element3546 may be configured to couple radiation from the radiation source3545 to the circular ring-shaped structure that guides the radiation toits exit point at the end of the catheter tube. Such optical shapingand/or control to properly couple the radiation into the circularring-shaped guide can be achieved using, for example, one or moreoptical elements, such as lenses, aspherical components, diffractiveoptical elements. Additionally, the required optical shaping and/orcontrol can also be implemented by mounting light sources with acircular shape or by using fiber illuminators to couple radiation fromthe radiation source to the guide. The guidance scheme depicted in thearrangement of FIG. 35 can be used without coating the tube 3551.

Alternatively, the outer wall 3549 of the catheter tube 3551, or theinner wall 3547 of the catheter 3551, or both, may be coated with areflecting coating. The reflecting coating may be covered by aprotection layer. In some embodiments, the catheter portion at which thelight is emitted out of the catheter tube is coated with a partiallyreflecting coating. In some embodiments, the catheter tube wall 3548 ismade of two layers with different indices of refraction such that theouter layer and the drug solution 3550 have smaller indices ofrefraction and thus serve as the claddings, while the inner layer of thewall 3548 serves as the waveguide core and guides the light. The secondouter layer may cover only the catheter portion at which the lightshould be guided and ends at the catheter portion at which the lightexits out of the catheter tube. In some embodiments, the tube wall 3548is made of three layers with different indices of refraction such thatthe outer layer and the inner layer have smaller indices of refractionand serve as the claddings, while and the middle layer of the wall 3548serves as the core to guide the light. The third outer layer may coatonly the catheter portion at which the light should be guided and endsat the catheter portion at which the light exits out of the cathetertube 3551 (not shown). In some embodiments, the reflection coefficientof at least one of the reflecting layers is gradually decreased at thecatheter portion at which the light exits out of the catheter tube toobtain more uniform illumination of the drug infused region (not shown).In some embodiments, the reflection coefficient of at least one of thereflecting layers is reduced in a specified profile at the catheterportion at which the light exits out of the catheter tube 3551 to get arequired illumination profile of the drug infused region.

Any of the above mentioned configurations for coupling or decoupling(scattering) the light out of the catheter end can be used with all ofthe various locations of the light source as described in differentherein. Referring to FIG. 36, showing another exemplary treatmentdevice, light can be guided in the catheter tube 3670 such thatradiation (e.g., light), represented schematically by the bouncing raylines, propagates in the drug containing fluid 3669 and/or in the tubewalls 3667 and/or in special layers or structures or waveguides insidethe tube 3670 or the tube wall 3667, or in any combination thereof. Thelight can be guided until it reaches the catheter end where it isemitted out through the same opening from which the drug is deliveredand infused into the body of the patient. As shown, the light isstrongly scattered in the tissue and illuminates a region having anapproximate spherical shape (not shown), with its center, for example,0.5-1 mm beneath the catheter tip (not shown). In some embodiments,light is emitted from within catheter 3670, through, for example, aradiation source 3665.

Similarly to some of the other device implementation described hereinwith respect to the other figures, the device shown in FIG. 36 mayinclude, for example, a catheter securing device 3664 with an adhesivelayer 3660. Additionally, drug is delivered through a drug delivery tube3661 from a drug delivery device (not shown) that an includes aconnector 3680 with sections 3662 and 3663 (similar to the sectionsshown in FIG. 33).

In some embodiments, a larger illuminated area is used, for example, toreduce the light intensity or lumens per unit area, for example, forsafety reasons. Therefore, in some embodiments, the light may be emittedthrough a larger portion of the catheter tube 3670. In some embodiments,the focused guidance of the light in the portion of tube 3670 within thetissue is reduced due, for example, to the contact of the catheter wall3667 with the tissue or due to the fact that the waveguide layers and/orstructures are altered to cause the light to leak out of the waveguideinto the adjacent tissue. As previously explained, alteration ofstructure and/or material of the waveguide layers can be used to controlthe profile of the illumination of the radiation at the drug infusedtissue area.

In addition to changing the properties of the layers and/or structures,additional refractive or diffractive elements can be added to thecatheter tube end to better control the spatial and angular distributionof the light emitted from the catheter end. For example, the inner side3666 of the catheter 3670 and/or the outer side of the catheter surfacecan be made rough or diffusive to scatter the emitted light 3668. Thesurface roughness of the catheter tube wall 3667 can be increased by,for example, embossing a pattern into the inner or outer sides. Suchpattern embossing may be done during the catheter tube manufacturingprocess or at the end of the manufacturing process, for example, bypressing a patterned cylindrical mold within or on the tube 3670, withsome heating that softens the tube polymer. In some embodiments, thelight angular and spatial distribution can be shaped by embossing adiffractive optical element pattern into the inner or outer sides.Diffraction optical element patterns, such as a grating, may be used forcoupling light into or out of optical waveguides. All or a portion ofthe light may be emitted out of the end of catheter tube 3670.

The device may provide illumination to the tissue both from inside thecatheter and through the skin by a combination of the techniques,structures and arrangements described herein.

The devices described herein (according to some embodiments) may haveshort range RF or IR communication with a data management and controlunit, such as a Personal Digital Assistant (PDA), a personal computer, acellular telephone and/or to a dedicated device that supports managingthe drug therapy. For example, if the drug is insulin, the data managingdevice may obtain the glucose readings from a glucose sensor, whethermanually or automatically, or by reading glucose sensing strips. Thedevice may also obtain information about consumed carbohydrates andother ingredients of food and/or drinks. The device may also storepatient history and relevant parameters, such as weight, BMI, insulinresistance and so forth.

The data managing device may also calculate the optimal required amountof insulin and the optimal tissue radiation profile. This informationcan be sent wirelessly to the drug delivery pump and/or to the radiationdevice (for providing electromagnetic radiation), for optimal drugdelivery. The radiation device may transmit tissue parameters measuredby sensors disposed on it to the data management and control unit asadditional information for determining one or more therapeuticparameters and/or for future statistics and data analysis. The datamanagement and control unit may recommend an optimal drug dosage andoptimal radiation profile to infused tissue region, which the patient(or other user) then approves before initiation of therapy. The datamanagement and control unit may recommend an optimal drug dosage. Insome embodiments, the data management and control unit may form part ofthe drug delivery pump.

Referring to FIG. 37, another exemplary treatment device with opticalsensors is shown. The treatment device includes, for example, twosensors 3785 and 3786 Fewer or additional sensors of different types maybe used. As further shown, the device of FIG. 37 includes a disposabledrug delivery pump configuration. In the depicted configuration, thedrug delivery pump 3782 and at least one light source 3783 are disposedin a single housing 3781 attached to the skin with adhesive layer 3780.

A light source 3783 generates light to illuminate the tissue. The lightis transferred to the tissue through catheter 3790 (the light is shownschematically by the bouncing ray line 3784). The two optical sensors3785 and 3786 measure the light passing through the catheter 3790. Lightis also reflected by a reflective coating for inner side 3787 of tubewalls 3788, although some may also scatter to the outside 3789 of tubewalls 3788.

The light exits at catheter tip 3791 into the tissue (not shown). Thelight is then scattered into and off the tissue and reaches the opticalsensors 3785 and 3786 through windows in the adhesive layer 3780 or, ifthe adhesive layer is transparent, through the adhesive layer.Measurements performed by the optical sensors 3785 and 3786 are used todetermine the amount of absorbed light (based on the fact that theinitial power of the light source is known). If wavelengths stronglyabsorbed by the hemoglobin such those as in the range of 600-1000 nm areused, the optical sensors 3785 and 3786 can provide information relatedto the hemoglobin concentration at the adjacent tissue region, which maythus provide information on the local blood perfusion. The bloodperfusion information can be used to monitor radiation level,distribution or wavelengths.

The absorbed light level can also be evaluated by measuring the lightwhich is back scattered into the optical waveguide formed by thecatheter tube 3790, guided by the waveguide and then coupled out of thewaveguide using the same coupling optics previously described, or byusing additional coupling optics into an optical sensor used formeasuring the back scattered light (not shown).

The above described methods, apparatus and devices for radiating thetissue are not limited to drug-delivery pumps, but can also be used withmanual delivery of the drug, such as connecting a syringe instead of apump to the proximal part of the catheter. Under such circumstances, thecatheter proximal part may terminate in a connector or a port that fitsthe syringe tip. The distal part of the catheter is inserted into thetissue as previously described in relation to the exemplarydrug-delivery arrangements.

Although the catheter was drawn with a 90° penetration angle in theabove embodiments, any suitable angle for catheter penetration may beselected. Smaller angles of penetration for the catheter may improve theattachment on one hand, but may also be more painful to insert.

It should be noted that whenever the local effect of the radiation orillumination of the tissue is described over the drug infused region,the radiation or illumination effect can also be applied to largervolume of tissue in the vicinity of the drug infused volume or tosmaller volume of tissue, depending on the specific treatment.

It should be noted that whenever ‘or’ is used in this document thechoice of the two or more detailed options is also possible. It shouldbe understood that certain features as described herein, which are, forclarity, described in the content of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures which are, for brevity, described in the context of a singleembodiment, may also be provided separately or in any suitablesub-combination.

Stimulated Drug Delivery Systems and Methods

In some embodiments, the present invention relates to devices forimproving, modifying and/or stabilizing pharmacokinetic and/orpharmacodynamic profile of a drug infused into the tissue by a catheterand absorbed into the blood or lymphatic system. The devices describedin some of the embodiments of the present application apply additionaltreatment or stimulation to the vicinity of the drug delivery site. Thetreatment can be one or combination of the tissue treatment treatmentsmodalities described in U.S. Ser. No. 11/812,230, such as: heating,modifying temperature, massaging, mechanical vibration, acousticvibration, ultrasound, suction, infusion of an additional substance orchemical, applying a low electric field, applying a low magnetic field,light irradiation, radiofrequency (“RF”) irradiation, microwave (“MW”)irradiation, etc. In some embodiments, the device has a catheter forinsertion within the tissue to infuse a substance into the infusedtissue region. The infused tissue region (i.e., the infused region) canbe one of the skin layers or the subcutaneous tissue or deeper tissueelements within any organ or viscera.

In many instances, the patients require insulin delivery around theclock to keep proper levels of glucose in their blood. Insulin can bedelivered at a basal rate or in bolus doses. The basal rate representsinsulin that is continuously delivered to the patient yet inpracticality is delivered in small intermittent boluses. Such continuousdelivery of insulin keeps the patient's blood glucose in the desiredrange between meals and over night. In many cases the basal insulin isdelivered by insulin pumps in short infusion pulses every 1-5 minutes.In some embodiments, tissue or skin treatments or stimulation methodscan be used to treat or stimulate a tissue region to which insulin isinfused during basal insulin delivery. One possible effect of the tissuetreatment, such as regulating the infused tissue region vicinity to aknown temperature, is improving the stability of the insulin absorptionto the circulatory system, and consequently improving the basal insulinpharmacokinetics pharmacodynamics stability. Another possible effect ofsuch a treatment is improving the efficiency of the absorption of theinsulin and consequently reducing the amount of infused insulin neededto achieve the desired metabolic effect.

In addition the diabetic patient needs to infuse insulin bolus doses formatching a the carbohydrates consumed during meals. When a patientconsumes food, his or her levels of glucose rise and the insulin bolusdose is supposed to match the rise in the level of glucose and toprevent large glucose excursions. However, many conventionalsubcutaneous drug delivery systems are incapable of quickly matching orpreventing the rise of blood glucose known as post prandialhyperglycemia. The delay in such matching is also true in case of the“rapid-acting” insulin analogs. Some of the reasons for this delayinclude a lag in the absorption of insulin from the injection site andthe time it takes for complex insulin molecules to break down intomonomers.

It is well known in the art that there are some adverse effects forinfusing large amounts of insulin which beside of regulating the glucoseabsorption has several additional hormonal effects, such as being growthfactor. In some cases, the excess amounts of insulin cause indirectly anundesired weight gain of diabetic patients, specifically those with atendency for developing hypoglycemia. In some cases the excess amountsof insulin at the infusion sight cause undesired local lipo-hypertrophy.

In some embodiments, tissue or skin treatments or stimulation methodscan be used to treat or stimulate a tissue region to which insulin isinfused during basal or bolus insulin delivery. One possible effect ofthe tissue treatment is improving the efficiency of the absorption ofthe insulin into the blood or lymph systems and consequently reducingthe amount of the insulin needed to create the desired metabolic effect.Consequently the undesired adverse effects of the excess insulin levels,such as excess weight gaining can be reduced. Anther possible effect ofthe tissue treatment is improving and reducing the amounts and thedurations that the insulin lasts at the tissue infused region, since itis absorbed faster in the blood or lymph systems. Consequently theundesired local adverse effects of the excess insulin levels, such asthe lipo-hypertrophy or local irritation can be reduced. Anther possibleeffect of the infused tissue region vicinity treatment is improving thelocal blood perfusion, which reduces the local inflammation effects ofthe infusion set or the puncturing or the insulin. Another possibleeffect of reducing the short and long term local effects of the insulinon the insulin infused tissue region is to lengthen the duration ofusing an infusion set on the same sight.

In some embodiments, tissue or skin treatment methods can be activatedon elective or preprogrammed boluses for brief periods to provide aboost of the insulin absorption. In some embodiments, tissue or skintreatments methods can be a part of all or some of the elements ofcomplex pre programmed boluses such as split wave, square root and otherbolus patterns. The stimulation can be activated for the initial phaseof a standard bolus, specifically for pre-programmed components of asplit bolus or at intervals of interest of the square bolus. In otherembodiments—the stimulation can be activated by a pre-programmed dutycycle independent of the bolus type. In other embodiments, theintermittent activation can be synchronized with individual boluscomponents of the basal rate.

In some embodiments, tissue or skin treatments or stimulation methodscan be used to treat or stimulate a tissue region to which a drug isinfused by an implanted drug or substance delivery device. In someembodiments, tissue or skin treatments or stimulation methods can beused to treat or stimulate a tissue region to which insulin is infusedby an implanted insulin delivery device. In some embodiments, implantedinsulin delivery device is an implanted insulin pump. In someembodiments, implanted insulin delivery device are implanted beta cellsthat can produce insulin. In case of implanted beta cells said tissuetreatment can support also the implanted cells, for instance byimproving local perfusion and improving the cells oxygen, glucose andother required ingredients supply. By improving the local perfusion alsothe beta cells or other glucose sensing element can react withoutunwanted delays to fast glucose variations.

In some embodiments, of implanted drug delivery device the tissuetreatment can be applied by the implanted device. An example isillustrated in FIG. 38. The implanted drug delivery device 3805 isimplanted in a tissue region 3802 underneath the skin 3801. Theimplanted drug delivery device has a catheter schematically shown by3803 for infusion of the drug into the tissue. In some embodiments, thedrug infusion to the tissue can be done using other modalities insteadof a catheter, such as, few catheters, or a large opening with amembrane on the drug delivery device side for infusing the drug into alarger volume of tissue and improving the drug absorption into thecirculatory or lymph system. The implanted drug delivery device has atreatment element, schematically shown by 3804 for applying treatment tothe drug infused region vicinity. The treatment can be one orcombination of the tissue treatment treatments modalities, such as:heating, modifying temperature, massaging, mechanical vibration,acoustic vibration, ultrasound, suction, infusion of an additionalsubstance or chemical, applying a low electric field, applying a lowmagnetic field, light irradiation, radiofrequency (“RF”) irradiation,microwave (“MW”) irradiation, etc.

In some embodiments, of implanted drug delivery device the tissuetreatment can be applied by a treatment device attached to the skin. Anexample is illustrated in FIG. 39. The implanted drug delivery device3915 is implanted in a tissue region 3913 underneath the skin 3912. Theimplanted drug delivery device has a catheter schematically shown by3914 for infusion of the drug into the tissue. In some embodiments, thedrug infusion to the tissue can be done using other modalities insteadof a catheter, such as, few catheters, or a large opening with amembrane on the drug delivery device side for infusing the drug into alarger volume of tissue and improving the drug absorption into thecirculatory or lymph system. The treatment device, schematically shownby 3911 is attached to the skin above the drug infused region forapplying treatment to the drug infused region vicinity. The treatmentcan be one or combination of the tissue treatment treatments modalities,such as: heating, modifying temperature, massaging, mechanicalvibration, acoustic vibration, ultrasound, suction, infusion of anadditional substance or chemical, applying a low electric field,applying a low magnetic field, light irradiation, radiofrequency (“RF”)irradiation, microwave (“MW”) irradiation, etc. The treatment device3911, can be attached to the skin in many methods, as described inapplication U.S. patent application Ser. No. 11/812,230, such asadhesive layer.

In some embodiments, glucose level regulation is obtained byautomatically controlling the insulin infusion rate using a continuousglucose sensor and a control algorithm. There are many attempts tocompose such an “artificial pancreas” since the development ofcontinuous glucose monitors. In this case, any delay such as the currentdelays of the insulin absorption and action time, any variability inthis delay and any variability in the residual insulin level in the bodyinduces an error for the control algorithm that will result in lesstight glucose regulation. Thus, by stimulating or applying a treatmentto the vicinity of the infused tissue region combined with input from animplanted or other types of glucose sensor and a control algorithm canprovide better accuracy and robustness of a closed loop glucose levelcontrol systems.

In some embodiments, the tissue in the vicinity of the glucose sensor istreated or stimulated by the above described treatments to improve theglucose transport form the blood system to the interstitial fluid andinto the glucose sensor, as described in U.S. provisional application60/948,472.

In some embodiments, the above described treatment or treatmentscombination is applied to the insulin infused tissue region vicinity andthe same or a different treatment or treatments combination is appliedto the vicinity of the tissue region in which the glucose level ismeasured by the glucose sensor. Therefore, both the delay of the glucosetransport to the ISF and to the sensor and the delay of the insulinpharmacokinetics and pharmacodynamics are reduced, enabling to achieve amore tight glucose regulation by closing the loop between the twodevices.

In some embodiments, the same treatment or treatments combination isapplied to the insulin infused tissue region vicinity and to thevicinity of the tissue region in which the glucose level is measured bythe glucose sensor.

In some embodiments, the tissue region in which the glucose level ismeasured by the glucose sensor is the in the vicinity of the insulininfused tissue region and the treatment or treatments combination isapplied to the vicinity of that tissue region with a single treatmentelement.

In some embodiments, described above both the insulin delivery deviceand the glucose sensor are implanted. In others, both are part of thesame transcutaneous catheter or part of a device that has more than onecatheter (one for infusion and one as a sensor) that are both insertedby one insertion process and are located in the proximity of each other.

In some embodiments, for automatic regulation of the glucose leveldescribed above, the processing unit or the algorithm includes anautomatic meal detection algorithm that identifies a rapid rise in theglucose level on a continuous glucose level signal. The processing unitinfuses insulin bolus using the insulin delivery device and applies theabove described treatment or treatments in case of detection of a mealand automatic detection. In others, the indication of food consumptioncan be given manually by the patient through the infusion pump.

In some embodiments, for semi automatic regulation of the glucose levelthat involves human approval for insulin bolus, the processing unit orthe algorithm includes an automatic meal detection algorithm thatidentifies a rapid rise in the glucose level on a continuous glucoselevel signal. The processing unit alerts the patient that infuses aninsulin bolus using the insulin delivery device and applies the abovedescribed treatment or treatments to shorten the insulin action time andreduce the postprandial glucose excursion.

In some embodiments, the treatment can be programmed to reduce thetemperature in order to reduce absorption of previously administeredinsulin that is still in the subcutaneous space. This feature can be acautionary and protective element of a closed loop system.

In some embodiments, the treatment can be in the vicinity of the druginfused tissue region and still induce the desired effect to the druginfused tissue region. For instance in the case of heating, W. Magerlet. al. [W. Magerl et. al. Journal of Physiology 497.3 pp 837-1848(1996)] showed that heating the skin can induce vasodilatation in humanat a distance of even 30 mm due to activation of nociceptive axonreflex. They also showed that in some cases short period heating canalso evoke vasodilatation for a period of few minutes. Therefore In someembodiments, the treatment, such as heating to temperature of 39.5° C.is applied for short periods of 2-60 seconds every few minutes andevokes vasodilatation that improves the drug pharmacokinetics and/orpharmacodynamics in the drug infused tissue region.

In some embodiments, the treatment can be calibrated for each patient tooptimize it for its own nociceptive axon reflex activation threshold.For instance, W. Margerl et. al. show that the vasodilatation evokingtemperature after 64 seconds of heating can vary between 37-143° C. fordifferent subjects. The calibration can be done also locally for aspecific infusion site. An method for calibrating the treatment deviceis to start applying the tissue treatment gradually in the firstinitiation of the treatment device and measure the treatment effect onthe tissue, such as vasodilatation, using a specific sensor connected tothe processor unit that controls the treatment device. Than theprocessing unit decide what level of tissue treatment to apply, tooptimize the treatment effect on one hand without causing any adverseeffects on the other hand. For example, in case the tissue treatment isheating and the desired effect is vasodilatation, the treatment devicecan gradually heat the tissue till the safety upper limit and measurethe local tissue vasodilatation. The vasodilatation can be measured byLaser Doppler Flowmetry (LDF). Another close parameter that can bemeasured is the tissue blood perfusion which can be measured by LDF orby one of the known in the art measurements for the tissue opticalabsorption in hemoglobin significant absorption lines, such as 700-1000nm. Afterwards, the processing unit uses that information to decide whatthe best peak temperature of the temperature heating profile to whichthe specific sight at the specific subject should be heated should be.

In some embodiments, these calibration process is repeated once a while,such as every 6-12 hours, to compensate for changes that might influenceon the temperature threshold of the axon reflex response to localheating.

In some embodiments, these calibration process is repeated every timethe treatment device is operated, such as during insulin bolus tocompensate for more rapid changes that might influence on thetemperature threshold of the axon reflex response to local heating, suchas Nitric Oxide, noradrenaline and other substances [Belinda et. al. J.Physiol. 572 3 pp 821-820 (1996)]. In this case when the treatment, suchas heating, is started the treatment parameter, such as temperature, israised gradually while measuring the desired tissue parameter such asvasodilatation, using LDF. When the vasodilatations happens thetreatment level, such as temperature, is stabilized to that level orslightly above it.

In some embodiments, these calibration process is repeated also duringthe treatment. In this case the treatment, such as heating, after itstarts as described in the paragraph above is regulated to keep thedesired tissue parameter, such as vasodilatation level stabilized to atarget level, during the whole treatment. Stabilizing the desired tissueparameter, such as vasodilatation level, stabilizes also the absorptionof drug in the blood and improve the repeatability of the drugpharmacokinetics and pharmacodynamics. Controlling the treatment levelaccording to the desired tissue parameter, such as vasodilatation levelmay reduce also the power consumption of the treatment device. Forinstance, in case of heating, since short period heating to a certaintemperature above the threshold temperature initiates the axon reflexresponse and vasodilatation, there is no need to keep the temperaturehigh for a long period and by that the power consumption can be reduced.

Systems and Methods for Drug Delivery Using Implanted Neural Stimulation

Referring now to the drawings, FIG. 40A-C use similar labels to refer tothe same functioning elements. FIG. 40A is a schematic block diagram ofan drug delivery device 4000 according to the present invention forcontrolled drug delivery to a target tissue. Drug delivery device 4000includes user interface 4002, communication module 4004, controller4006, drug delivery module 4008, drug compartment 4010, tissue treatmentelement 4014, external drug supply 4012, and sensor 4016. Device 4000 isimplanted within the body and provides an improved controllable drugdelivery system. The implantation site may vary and is chosen dependingon the target tissue and the drug being delivered. For example, device4000 may be implanted subcutaneously or near the digestive tract for aninsulin drug delivery system. However, if device 4000 includes a drugfor the cardiovascular system, device 4000 may, for example, beimplanted in a subcutaneous cavity in the vicinity of the cardiovascularsystem.

Sensor 4016 may not be implanted and is an independent external device,as is known and accepted in the art, that is used to monitor a measurandrelative to the drug being delivered, for example including but notlimited to a glucose sensor that indicates the glucose levels at thetime of the test. At least one or more sensors may be used to measure aplurality of parameters relating to the drug being delivered. Themeasurements sensed by sensor 4016 are relayed to controller 4006,through user interface 4002 and communication module 4004 (for example).The controller 4006 depicts the action to be taken relative to thesensed results; the action to be taken may be the absence of an action.User interface 4002 may communicate instructions and protocols tocontroller 4006 using the communication module 4004. Controller 4006 mayintrinsically include various treatment protocols, and historical datarelative to the different situation sensed by at least one or moresensor 4016. Controller 4006 may employ learning algorithms, for exampleincluding but not limited to artificial intelligence means to adjust oradapt the treatment protocols to be more specific or tailored to thedrug delivery needs and eating habits of the patient using device 4000.

Controller 4006 controls and overseas the performance of the drugdelivery module 4008 and tissue treatment element 4014 with respect tothe parameters sensed by at least one or more sensor 4016. Drug deliverymodule 4008 may include at least one or more catheters that is/are usedto deliver the drug to the targeted site. The drug delivery may beundertaken with a selective membrane that allows the drug to be safelydelivered to the target tissue over a larger surface area.

Drug delivery to the target tissue is mediated by controller 4006 thatuses the drug storage compartment 4010 to delivery the drug via drugdelivery module 4008. Drug storage compartment 4010 contains sufficientquantities of the drug to last a prolonged period of time, for exampleseveral months. When drug quantities are depleted and need to bereplenished, controller 4006 may communicates via communication module4004 to user interface 4002 regarding the need for replenishment. Thedrug supply may be replenished from an external source 4012 that isdirectly linked to the implanted drug storage container 4010. The linkbetween drug storage 4010 and drug source 4012 may, for example, bemediated by a mechanism including but not limited to one or more of areusable catheter, an injection, or the like.

Tissue treatment element 4014 is used to stimulate or inhibit the tissuetargeted site to increase drug absorption, more by increasingvasodilatation, or by employing a mechanism to improve drug uptake thatis specific to the drug being delivered and the target site itself.Tissue treatment element 4014 may be used on the drug itself, providingfurther control where drug properties are changed to increase ordecrease its relative activity. Tissue treatment element 4014 may bestimulated by modes including but not limited to one or more oftemperature change, optical, IR irradiation, RF irradiation, microwaveirradiation, ultrasound, massaging, or the like. Tissue treatmentelement 4014 may stabilize the tissue targeted site to reduce thevariability of the drug absorption into the circulatory system.

Controller 4006 may include a database (not shown) that contains varioustreatment protocols specific to one or more different metabolicparameters that are sensed by sensor 4016. Changes, updates to thedatabase, and/or treatment protocols within controller 4006, may beintroduced from external resources through communication module 4004.Communication module 4004 may be able to both send and receive updatesto and from an external user interface 4002 or like source, for exampleincluding but not limited to a PDA, computer, server, cellular telephoneor the like. Communication with communication module 4004 may bemediated by communication protocols for example including but notlimited to cellular, wireless, optical, IR (infrared), RF(radiofrequency), or the like communication protocols; communicationprotocols used may be encrypted.

FIG. 40B is an embodiment of the drug delivery device according to thepresent invention that functions similarly to that depicted in FIG. 40A,however, the tissue treatment element 4034 is not implanted but ratheris employed at or on the external skin surface. Treatment element 4034may be adhered to the skin and functions externally.

Tissue treatment element 4034 is used to indirectly stimulate or inhibitthe tissue targeted site by applying an appropriate treatment on theexternal surface. The employed treatment protocol controls drugabsorption, more by controlling vasodilatation, or by employing amechanism to improve drug uptake that is specific to the drug beingdelivered and the target site itself. Tissue treatment element 4034 mayfunction by different modes including but not limited to one or more oftemperature change, optical, IR irradiation, RF irradiation, microwaveirradiation, ultrasound, massaging, or the like. Tissue treatmentelement 4034 may stabilize the tissue targeted site to reduce thevariability of the drug absorption into the circulatory system.

FIG. 40C depicts another embodiment of the drug delivery systemaccording to the present invention wherein a plurality of tissuetreatment elements are employed, wherein at least one or more elementsinclude one or more implanted tissue treatment elements 4014 and atleast one or more elements include one or more external tissue treatmentelements 4034. The implanted and nonimplanted treatment elements 4014and 4034 combination provides further control of the applied treatmentdirectly or indirectly to the target tissue site.

FIG. 40D depicts another embodiment of the drug delivery systemaccording FIG. 40A wherein a sensor is not utilized. Drug deliverysystem 4000 delivers the appropriate medicament to the tissue targetsite independent of sensed information; rather, delivery system 4000functions according to data obtained from user interface 4002 and/or byoperation of controller 4006. In this embodiment, drug delivery module4008 functions based on the schedule or protocols provided by controller4006 and/or indirectly from user interface 4002, as described in FIGS.40A-C. Similarly, neither of the implanted tissue treatment element 4014or external issue treatment element 4034 (shown as stimulator 4034)function based on sensed information; rather both function according toone or more protocols obtained from either user interface 4002 orcontroller 4006.

FIG. 41A is a depiction of an embodiment of the present inventionaccording to FIG. 40A where the tissue treatment element 4112 isimplanted and located internally to skin 4111. Tissue treatment element4112 is used to treat the tissue layer to improve the pharmacokineticand/or pharmacodynamic properties of the targeted tissue. In someembodiments, drug storage compartment 4108 provides the drug to bedelivered to the delivery module 4106 and thence to delivery member4120. In some embodiments, for example for tissue treatment thatinvolves direct or indirect heating and temperature sensitive drugs,such as insulin, where some types of insulin are preferred to be storedat less than 37° C., the drug storage compartment 4108 is thermallyisolated, to keep the drug at the proper temperature during the tissuetreatment. The drug may be delivered to the storage compartment 4108 bydirect injection through membrane 4104. Tissue stimulation protocols anddrug delivery protocols may be communicated to the controller (notshown) via user interface 4116.

FIG. 41B is a depiction of an embodiment of the present inventionaccording to FIG. 40B where the tissue treatment element 4102 is locatedexternally to skin 4111 and is not implanted. Tissue treatment element4102 may be attached to the skin via an adhesive layer and/or a strap(not shown). Tissue treatment element 4102 is used to treat the tissuelayer to improve the pharmacokinetic and/or pharmacodynamic propertiesof the targeted tissue. Drug storage compartment 4108 may provide thedrug to be delivered to the delivery module 4106 and thence to deliverymember 4120. In some embodiments, for example for tissue treatment thatinvolves direct or indirect heating and temperature sensitive drugs,such as insulin as noted above, the drug storage compartment 4108 isthermally isolated, to keep the drug at the proper temperature duringthe tissue treatment. Drug may be delivered to the storage compartment4108 by direct injection through membrane 4104.

FIG. 41C is a depiction of an embodiment of the present inventionwherein the drug is produced externally and introduced to the implantedportion via drug transfer catheter 4114. Tissue treatment element 4102may be located externally to skin 4111. Tissue treatment element 4102may be attached to the skin via an adhesive layer (not shown). Tissuetreatment element 4102 is used to stimulate or inhibit the tissue layerto improve the pharmacokinetic and/or pharmacodynamic properties of thetargeted tissue. In some embodiments, as noted above for tissuetreatment that involves direct or indirect heating and temperaturesensitive drugs, such as insulin, the drug storage compartment 4108 isthermally isolated, to keep the drug at the proper temperature duringthe tissue treatment. Catheter 4114 may be used to fill drug storagecompartment 4108 in an implanted layer 4113 once replenishment is neededas determined by the controller (not shown). An indication of druglevels within compartment 4108 may be provided by controller (not shown)to a visual cue 4116 for example including but not limited to a userinterface or LED. The drug is delivered through delivery member 4120 asshown.

FIG. 41D is a depiction of an embodiment of the present inventionaccording to FIGS. 40D and 40C where there may be a plurality of tissuetreatment elements, an external element 4102 located externally to skin4111 and an implanted element 4112 located in the implanted layer 4113.Tissue treatment element 4102 may be attached to the skin 4111 via anadhesive layer (not shown). Tissue treatment elements 4102 and 4112 areused to treat the tissue layer to improve the pharmacokinetic and/orpharmacodynamic properties of the targeted tissue. In some embodiments,for example as noted above for tissue treatment that involves direct orindirect heating and temperature sensitive drugs, such as insulin, thedrug storage compartment 4108 is thermally isolated, to keep the drug atthe proper temperature during the tissue treatment. Drug storagecompartment 4108 may provide the drug to be delivered to the deliverymodule 4106 and thence to delivery member 4120 that may be a membraneable to deliver drug over a larger surface area. The drug may bedelivered to the storage compartment 4108 by direct injection throughreceiving membrane 4104.

FIG. 42 is a flow chart of the closed loop drug delivery device havingand internal drug reservoir. The drug reservoir can be replenished usingan external drug source as needed. In stage 4200 the device is implantedin a patient (subject) at a chosen tissue target site. In stage 4202 atleast one or more sensors detect cellular and/or biological parameters,for example including but not limited to glucose levels. In stage 4204the controller determines the action to be taken based on the sensordata obtained in stage 4202. In stage 4210 the controller may activate atissue treatment element to initiate a stimulation or inhibitionprocedure using any one of its modes for example including but notlimited to heat, cold, temperature change, ultrasound, optical, massage,physical stimulation, vibration, suction, IR, microwave, RF, optical, orthe like. This stage may also include the absence of action. In someembodiments, stimulation is and optimized according to the user's ownnociceptive axon reflex activation threshold.

In stage 4208 the controller may indicate that the drug supply isdepleted and that drug replenishment is required, to an externalindicator. The indication may be accomplished via an user interface, LEDor the like. In stage 4206, a drug dosage form is determined and definedto be delivered to the tissue target site in stage 4212. Stages 4202,4210 and 4212 are in a feedback loop that may continuously control thedrug delivery process, or at least may be performed with a plurality ofrepetitions, in order to safeguard that the desired or appropriate druglevels are maintained at the target site.

FIG. 43A is a schematic block diagram of a drug delivery device 4300according to the present invention for controlled drug delivery to atarget tissue. Drug delivery device 4300 includes tissue treatmentelement or tissue treatment element 4302 (shown as stimulator 4302),controller 4304, sensor 4306, drug production module 4308, drug deliverymodule 4305 and communication module 4307. Device 4300 is implantedwithin the body and provides a closed loop drug delivery system. Theimplantation site may vary and is chosen dependent on the target tissueand the drug being delivered. For example, a device 4300 may beimplanted subcutaneously or near the digestive tract for an insulin drugdelivery system. However, if device 4300 included a drug for thecardiovascular system it may for example be implanted in a subcutaneouscavity in the vicinity of the cardiovascular system.

Sensor 4306 continuously or at least repeatedly and/or periodicallymonitors a measurand relative to the drug being delivered, for exampleincluding but not limited to a continuous glucose sensor that indicatesthe glucose levels at any given moment. At least one or more sensors maybe used in conjunction to measure a plurality of parameters relating tothe drug being delivered. The measurements sensed by sensor 4306 arerelayed to controller 4304 that depicts the action to be taken relativeto the sensed results; the action to be taken may be the absence of anaction. Controller 4304 may include various treatment protocols, andhistorical data relative to the different situation sensed by at leastone or more sensors 4306. Controller 4304 may also employ learningalgorithms, for example including but not limited to artificialintelligence means to adjust or adapt the treatment protocols to be morespecific or tailored to the drug delivery needs and eating habits of thepatient using device 4300.

Controller 4304 controls and overseas the performance of the drugproduction module 4308, drug delivery module 4305 and tissue treatmentelement 4302 with respect to the metabolic parameters sensed by at leastone or more sensors 4306. Drug delivery module 4305 may include at leastone or more catheters that is/are used to deliver the drug to thetargeted site. The drug delivery may be undertaken with a selectivemembrane that allows the drug to be safely delivered to the targettissue.

Tissue treatment element 4302 is used to stimulate or inhibit the tissuetargeted site to increase drug absorption, more by increasingvasodilatation, or by employing means to improve drug uptake that isspecific to the drug being delivered and the target site itself. Tissuetreatment element 4302 may be used on the drug itself, providing furthercontrol where drug properties are changed to increase or decrease itsrelative activity. Tissue treatment element 4302 stimulates by modesincluding but not limited to temperature change, optical, IRirradiation, RF irradiation, microwave irradiation, ultrasound,massaging, or the like. Tissue treatment element or tissue treatmentelement 4302 stabilizes the tissue targeted site to reduce thevariability of the drug absorption into the circulatory system.

Drug production module 4308 includes cells that may produce the drug,for example including but not limited to insulin that is to be deliveredto a target site. Drug production module 4308 includes at least one ormore of beta cells, other cells, tissue culture and/or bacterial culturecapable of producing insulin. Drug production by module 4308 iscontrolled by controller 4304.

Controller 4304 includes a database (not shown) that contains varioustreatment protocols specific to different metabolic parameters sensed bydelivery device 4300. Changes, updates to the database, and/or treatmentprotocols within controller 4304 may be introduced from externalresources through communication module 4307. Communication module 4307is able to both communicate the status of device 4300 and to receiveupdates to and from an external source for example including but notlimited to a PDA, computer, server, cellular telephone or the like.Communication is mediated by communication protocols for exampleincluding but not limited to cellular, wireless, optical, IR, RF, or thelike communication protocols; communication protocols used may beencrypted.

For example, when continuous glucose readings from sensor 4306 asprocessed by controller 4304 indicate that the blood sugar level isrising at an increased rate, controller 4304 then indicates to drugproduction module 4308 to begin or increase insulin production at arequired rate. Similarly, controller 4304 utilizes tissue treatmentelement 4302 to initiate target tissue stimulation while drug deliverymodule 4305 is used to delivery the drug to the target site at anappropriate rate so as to maximize tissue absorption in a timely anddose specific manner. Controller 4304 may implement different drugdelivery protocols based on new protocols communicated from an externalsource via communication module 4307. As sensor 4306 continues tomonitor the various metabolic parameter(s), changes are implemented in afeedback loop manner that best suits the metabolic needs of the patient.

FIG. 43B depicts a schematic block diagram of an embodiment of theimplanted drug delivery device 4300 according to the present inventionas depicted in FIG. 43A and having an external user interface 4301. Userinterface 4301 communicates to drug delivery device 4300 using acommunication protocol for example including but not limited to cellulartelephony, wireless, optical, IR, RF or the like communication protocol.User interface 4301 communicates to controller 4304 data relating to anyone of device 4300 components. For example, user interface 4301 maytrigger insulin production or delivery (or other drug production ordelivery) through drug production module 4308 and/or drug deliverymodule 4305, respectively, by way of communication with controller 4304.Similarly, user interface 4301 may indicate a particular stimulationprotocol to be performed by using tissue treatment element 4302.

FIGS. 44A-C are embodiments of device 400 depicted in FIGS. 43A-C. FIG.44A depicts device 4400 that is implanted subcutaneously beneath theskin layer 4401, therefore implanted layer 4413 is below the skin layer4401 while external layer 4411 is outside skin layer 4401. Implantationmay be achieved by subcutaneous injection, keyhole surgery, or surgeryperformed with local anesthesia or the like. Device 4400 includes acatheter 4410 that delivers the drug to a target site.

Drug delivery and the pharmacokinetic and pharmacodynamic properties aredifferentially controlled with tissue treatment element 4412 that morestimulates tissue through one or more treatment methods for exampleincluding but not limited to heat, temperature control, micro massage orphysical or vibrational stimulation, ultrasound, RF, IR, opticalirradiation or any combination of them or the like. Tissue treatmentelement 4412 may stimulate the drug directly, to control its properties;for example, the insulin may be kept at a constant temperature to ensurethat it is in active and viable form while the surrounding tissue isstimulated by heat. Controller 4414, sensor 4416, and drug productionmodule 4418 are incorporated into device 4400 and function as depictedin FIGS. 43A and 43B.

The closed loop drug delivery system 4400 uses at least one or moresensors 4416 to determine the metabolic parameters; where controller4414 utilized the sensor parameters to determine the appropriate actionto take. For example, controller 4414 may trigger the drug productionprocess with the drug production module 4418. Once the drug is producedand is ready for delivery controller 4414 activates tissue treatmentelement 4412 to prepare the target tissue for drug delivery which isaccomplished via catheter 4410. Drug delivery catheter 4410 may come indifferent forms as depicted in FIGS. 44B-44C. As the drug is absorbed bythe target site it brings about changes in the metabolic parameters thatare sensed by at least one or more sensors 4416, of which one is shownfor the purpose of explanation only and without any intention of beinglimiting. The change in the data is then communicated to the controller4414 to bring about an adjustment in the treatment protocol andtherefore differentially control the different components, for exampleincluding drug production module 4418 and/or tissue treatment element4412.

FIG. 44B depicts an implementation of an implanted delivery module aspreviously described. Delivery device 4409 includes a plurality ofcatheters 4417, 4418, 4419 and 4420 that introduce a drug over a largerarea within the target site. The plurality of catheters 4417-4420 mayfurther encase at least one or more sensors 4426 or a tissue treatmentelement 4422 that sense and stimulate the tissue target site.

FIG. 44C depicts an implementation of an implanted delivery module aspreviously described. The delivery method is achieved with the use of aselectively permeable member 4430 that delivers the drug to the targettissue through a larger surface area, therefore further improving thedrug absorption into the blood system.

Neural Stimulation of Tissue During Drug Delivery

Referring now to the drawings, FIG. 45 is a schematic block diagram ofan drug delivery device 4500 that may be used with the neuralstimulation method according to the present invention for controlleddrug delivery to a target tissue having controllable tissue neuralstimulation. Drug delivery device 4500 includes controller 4502,database 4504, tissue treatment element 4508 and sensors 4506. Aplurality of other components, such as tissue treatment element 4518 andsensor 4516, may not associated with the drug delivery device 4500. Drugdelivery device 4500 may be placed in different locations, including butnot limited to transcutaneously, subcutaneously, implanted orexternally. The placement of drug delivery device 4500 is dependent onthe treatment and drug to be delivered.

In some embodiments, neural stimulation treatment protocol is stored indatabase 4504 and is accessible by controller 4502 to determine theneural stimulation treatment protocol to be used. Controller 4502 isused to activate tissue treatment element 4508 to initiate treatment atthe tissue delivery site. Sensor 4506, which may for example beimplemented for Laser Doppler Flowmetry (LDF), is used to measure theefficacy of the treatment evoked by tissue treatment element 4508.Sensor 4506, tissue treatment element 4508 and controller 4502 arefunctionally integrated to bring about a desired effect, more based onthe neural stimulation treatment protocol stored in database 4504.

Additional sensors 4516 and tissue treatment element 4518 may be placedat locations at a distance from device 4500. Incorporating sensor 4516and treatment element 4518 provides for additional control of thetreatment protocol in some embodiments. Further, sensor 4516 andtreatment element 4518 may be placed at different tissue site(s) fromsensor 4506 and element 4508, thereby allowing device 4500 andcontroller 4502 to measure and control and calibrate the neuralstimulation based on data obtained over a larger area.

Additional treatment element 4518 may be a different type of elementthan that of element 4508, thereby allowing for a plurality of differenttypes of treatment elements to be used with device 4500. For example,element 4508 may be used to introduce an electric current while element4518 may be used to introduce heat. As another non-limiting example,element 4508 may be used to introduce heat while element 4518 may beused to introduce cold. Optimally the use of a plurality treatmentelements (such as the non-limiting example of two elements 4508 and4518) may allow for increased individualization of the axon reflextreatment protocol over a larger area.

Sensors 4516 and 4506 may be used to measure different measurands toprovide more control of device 4500. For example, sensor 4516 may be aLaser Doppler Flowmetry (LDF) measuring vasodilatation while sensor 4506may be heat sensor measuring tissue temperature.

FIG. 46 is a flowchart that depicts the calibration processes accordingto some embodiments or methods of the present invention. In stage 4600the device is calibrated to the user where tissue treatment site, typeof drug and indicated to the delivery device to evoke the correcttreatment protocol. Furthermore, personal data such as comfort level maybe set by the user. The limits and parameters defined in stage 4600 areset in stage 4602 and incorporated into the delivery device. In stage4604 the initial treatment is implemented by the controller 102 of FIG.45 and at least one or more sensors, which may, for example, beimplemented with Laser Doppler Flowmetry (LDF), is used to monitor theadvancement of the treatment process as the treatment protocol advances.In stage 4606 the parameters for example including but not limited to,burst timing, timing and length of resting period, heat levels,temperature or current type, and the like, are measured and may bealtered to bring about the effects relative to the elapsed time andwhere treatment effects such as vasodilatation levels or thresholdlevels are relative to expected levels.

In stage 4608 the treatment may be altered according to a learningalgorithm (for example) known in the art, for example including but notlimited to a PID (proportional-integral-derivative) controller,artificial intelligence mechanism, or the like to adjust or adapt thetreatment protocols to be more specific or tailored to the drug deliveryneeds of the user.

In stage 4610 the altered treatment according to the learning algorithmis tested using feedback control that may be repeated with earlier stage4602, which may include positive feedback 4612 for certain parameters ornegative feedback 4614 for other parameters. Positive and negativecontrols are used to reset and alter old protocols, and may be used toadjust new parameters or treatment protocols for future use in stage4602. Different treatment protocols may stored by the database 104 ofFIG. 45, for different situations.

The calibration protocol depicted above may be implemented one time fora specific user only using stages 4600-4604, while all of the stages maybe used when treatment is implemented once a day, at every drug deliveryevent, or in a dynamic process as necessary.

FIG. 47 presents a flow chart depicting the neural stimulation treatmentprotocol and the interaction of the sensor and treatment element tocontrol the various parameters, and may include (but not limited to) oneor more of burst timing, timing and length of resting period, heatlevels, temperature or current type, heating power, time for temperatureto increase or decrease, that may be controllably changed to personalizethe treatment protocol relative to the user. Controller 4502 of FIG. 45initiates activity of at least one treatment element of FIG. 45, forinitiating treatment in stage 4700.

The tissue treatment implemented is the axon reflex according to knownprotocols, may be stored in database 4504 described in FIG. 45. Tissuetemperature is gradually increased to an upper limit more based on theuser's comfort level and may be, according to one or more tissuedependent temperature limits, for example 43° C. for skin, according tosafety standards that are known in the art. The temperature rise occursover a predetermined period of time, for example 64 seconds, to cause atemperature increase from 37° C. to 43° C. Alternatively, an oscillatingheat burst may be implemented to bring about the overall neuralstimulation temperature increase; treatment may be performed accordingto a 2-5 ratio, featuring 2 seconds of temperature increase and a 5second resting period, or as known and accepted in the art. Thetreatment protocol to bring about the axon reflex by heat induction maybe further dependent on the location of the treatment element, which maybe implanted or external, and also on the tissue being stimulated.

In some embodiments, as heat and other treatments are introduced instage 4700, a sensor records the changes in the temperature, andmonitors vasodilatation, and may include the rate of change oftemperature and/or dilation, in stage 4702. As the sensor records thechange in vasodilatation, and temperature, controller 4502 of FIG. 45,and more continuously, may determine whether the vasodilatationthreshold has been reached in stage 4704.

In stage 4706, if a threshold has been reached, then the controllerperforms any function(s) required to limit or reduce the treatmentelement activity to regulate treatment. If the threshold has not beenreached and vasodilatation has not reached required levels to bringabout an improvement in drug pharmacokinetic and pharmacodynamicproperties, then controller 4502 of FIG. 45 may increase the activity oftreatment elements in stage 4700 within the limits known and accepted inthe art to bring about the required level of heat and vasodilatation.

FIG. 50 presents a flow chart depicting a method for controlling thetemperature of heating provided by a treatment element in order toprevent degradation of a temperature sensitive drug, according to someembodiments of the present invention. As shown in step 5000, a drug isprovided for administration to the patient, which is sensitive todegradation above a limiting temperature. In step 5001, a treatmentelement is provided which features controllable heating through acontrollable heating element. In step 5002, the treatment element isplaced in temperature communicative contact with the tissue to beheated, such that heat from the treatment element is transferred to thetissue to be heated.

In step 5003, the maximum temperature provided by the treatment elementis controlled, such that the temperature experienced by the drug (thatis, in the environment of the drug) does not exceed the limitingtemperature sustainable by the drug before degradation occurs. Themaximum temperature can be calibrated for each drug and/or class ofdrugs. For example, for some types of insulin, the limiting temperatureis about 37° C.

Such control can be provided through a microprocessor or other processorfor controlling the temperature output by a heating element. A sensormay also be provided in order to measure the temperature at the tissuebeing heated, in order to determine the temperature experienced by thedrug.

In some embodiments, the treatment element includes one or morematerials capable of generating an exothermic reaction, in which theamount of such materials and/or ratio is calculated in order for thetemperature of the reaction to not exceed the maximum temperature setfor the treatment element according to the desired limiting temperatureof the drug. The exothermic reaction can be a heat-generating oxidationreaction, for example, using a mixture of iron powder, activated carbon,salt and water. As can be understood by one skilled in the art, othermixtures and/or materials can be used.

While the invention has been described with respect to a limited numberof embodiments, it will be appreciated that many variations,modifications and other applications of the invention may be made. Anyand all patents, patent applications, articles and other published andnon-published documents referred to anywhere in the present disclosureis herein incorporated by reference in their entirety. It should benoted that whenever the local effect of the treatment is described overthe drug infused region, the treatment effect can be also on largervolume in the vicinity of the drug infused volume or on a smallervolume, depending on the specific treatment.

Although particular embodiments have been disclosed herein in detail,this has been done by way of example and for purposes of illustrationonly, and is not intended to be limiting. In particular, it iscontemplated by the inventors that various substitutions, alterations,and modifications may be made without departing from the spirit andscope of the disclosed embodiments. Other aspects, advantages, andmodifications are considered to be within the scope of the disclosed andclaimed embodiments, as well as other inventions disclosed herein. Theclaims presented hereafter are merely representative of some of theembodiments of the inventions disclosed herein. Other, presentlyunclaimed embodiments and inventions are also contemplated. Theinventors reserve the right to pursue such embodiments and inventions inlater claims and/or later applications claiming common priority.

1-346. (canceled)
 347. A system for delivering a therapeutic substanceinto the body of a patient, comprising: a drug delivery device includinga drug delivery pump coupled to a drug reservoir containing thetherapeutic substance; and a detection unit coupled to the drug deliverypump, the detection unit including a sensor for detecting delivery ofthe therapeutic substance; an infusion set including an infusioncatheter for insertion into the body of the patient; a tube connectingthe infusion catheter with the drug delivery device and configured toallow delivery of the therapeutic substance from the drug deliverydevice to the infusion catheter; a treatment element for applyingtreatment to a region on the body of the patient in which thetherapeutic substance is infused; and a control unit for initiating apredetermined treatment profile using the treatment element when thedrug delivery device starts drug infusion; at least one power source forpowering at least one of the drug delivery device and the infusion set;wherein the detection unit is configured to transmit a wirelesscommunication signal to the control unit upon detection of the deliveryof the therapeutic substance, the wireless communication signal isindicative of at least a rate at which the therapeutic substance isbeing delivered to the body of the patient; wherein the control unit isconfigured to initiate the predetermined treatment profile based on atleast the rate at which the therapeutic substance is being delivered tothe body of the patient.
 348. The system according to claim 347, whereinthe therapeutic substance is selected from a group consisting of:insulin, insulin analogues and insulin mimetics.
 349. The systemaccording to claim 347, wherein the treatment is applied short timebefore, during and/or after an infusion of the therapeutic substance.350. The system according to claim 347, wherein the treatment isconfigured to modify pharmacokinetic and/or pharmacodynamic profile ofthe therapeutic substance; wherein the pharmacokinetic and/orpharmacodynamic profile of the therapeutic substance is modified toperform at least one of the following actions: enable a faster onset ofaction of the substance infused into the infused region; enable a fasterpeak of action of the substance infused into the infused region; enablea faster clearance of the therapeutic substance from the infused regionto the circulatory system of the patient; improve the repeatability ofthe pharmacokinetic and/or pharmacodynamics profile in response to theinfusion of the therapeutic substance; to reduce a variability ofabsorption of the therapeutic substance into the blood system and/orlymphatic system of the patient; to reduce a variability of onset ofaction of the therapeutic substance; to reduce a variability of time topeak of action of the therapeutic substance; and to reduce a variabilityof the clearance of the therapeutic substance from the infused region tothe circulatory system of the patient.
 351. The system according toclaim 347, wherein the rate at which the therapeutic substance is beingdelivered is selected from a group consisting of: a bolus rate and abasal rate.
 352. The system according to claim 347, wherein thetreatment is selected from a group consisting of: a heating deviceconfigured to heat the infused region; an optical radiation deviceconfigured to irradiate the infused region with optical radiation; amicrowave generator or emitter configured to irradiate the infusedregion with microwave radiation; a radio frequency electromagneticradiation generator or emitter configured to irradiate the infusedregion with radio frequency electromagnetic radiation; a vibrationdevice configured to vibrate and/or massage the infused region; a vacuumdevice configured to apply suction to the infused region; an electricfield generator and/or emitter configured to apply an electric field tothe infused region; a magnetic field generator or emitter configured toapply magnetic field to the infused region; and an acoustic signalgenerator and/or emitter configured to apply acoustic stimulation to theinfused region.
 353. The system according to claim 347, wherein thetreatment device is configured to apply one or more additionalsubstances to the infused region wherein the one or more additionalsubstances is configured to perform at least one of the followingactions: modify the pharmacokinetic and/or pharmacodynamic profile ofthe therapeutic substance; modify absorption of the therapeuticsubstance into the blood system and/or lymphatic system of the patient;and promote clearance of the therapeutic substance from the infusionregion.
 354. The system according to claim 347, wherein the treatmentelement is a heater element configured to apply heat to the infusedregion.
 355. The system according to claim 354, further comprising athermostat for automatically regulating a heating temperature at whichheat is applied by the heater element to the infused region, the heatingtemperature is being detected by a temperature sensor disposed in thethermostat; wherein the thermostat is configured to increase and/ordecrease power supplied to the heater element based on the temperaturedetected by the temperature sensor.
 356. The system according to claim354, wherein the infused region is heated to a temperature that does notdamage the therapeutic substance.
 357. The system according to claim354, wherein the heater does not heat the drug reservoir.
 358. Thesystem according to claim 354, wherein the heater element is configuredto heat the infused region without heating the therapeutic substanceabove a limiting temperature prior to infusion of the therapeuticsubstance into the infused region, or prior to the therapeutic substancebeing infused into an end of the infusion catheter.
 359. The systemaccording to claim 358, wherein the limiting temperature is about 37degrees C.
 360. The system according to claim 354, where the controlunit is configured to regulate heating of the infused region tostabilize a temperature of the infused region at a predeterminedtemperature.
 361. The system according to claim 360, wherein thepredetermined temperature is between about 37 degrees C. and about 42degrees C.
 362. The system according to claim 360, wherein, wherein thepredetermined temperature is between about 37 degrees C. and about 39degrees C.
 363. The system according to claim 360, wherein, wherein thepredetermined temperature is between about 32 degrees C. and about 37degrees C.
 364. The system according to claim 354, wherein the heaterelement is configured to apply heat subsequent to an infusion of a bolusdose of the therapeutic substance for a period of between about 10minutes and about 30 minutes.
 365. The system according to claim 354,wherein the heater element is configured to apply heat subsequent to aninfusion of a bolus dose of the therapeutic substance for a period ofbetween about 1 minutes and about 10 minutes.
 366. The system accordingto claim 347, further comprising a glucose level sensor for detectingglucose level in the body of the patient; wherein the control unit isconfigured to receive the detected glucose level reading from theglucose level sensor and further configured to control by way of analgorithm an infusion rate of the therapeutic substance into the infusedregion and the treatment element to regulate the glucose level in thebody of the patient.